Pulmonary Arterial Hypertension
Translational Research Improves Prognosis
ABSTRACT: Better definition of pulmonary arterial hypertension, improved diagnostics, enhanced understanding of pathogenesis, and targeted new drugs are improving prognosis.
CME OBJECTIVE: The reader will understand the pathogenetic-clinical links in pulmonary arterial hypertension and the rationale for approved therapies.
Raymond L. Benza, MD, consultant: Adelion, United Therapeutics
Less than a decade ago, few effective options existed for patients with pulmonary arterial hypertension (PAH). Now, breakthroughs in medical therapy offer improved prognosis and quality of life, says Raymond L. Benza, MD, director of the UAB Pulmonary Vascular Disease (PVD) Program in the Division of Cardiovascular Disease. This program interfaces with an extensive clinical program for evaluation and treatment of PAH and pulmonary hypertension caused by thromboembolic disease.
"In patients with PAH, the pulmonary vasculature and the right ventricle undergo structural changes," Benza explains. "Caused by abnormal interactions between pulmonary endothelial and smooth muscle cells, vascular remodeling and massive medial thickening narrow pulmonary arterioles, elevate pulmonary arterial pressure, diminish pulmonary circulation, and result in right ventricular hypertrophy. If left untreated, the enlarged right ventricle will eventually weaken, leading to right heart failure and death.
"Before the advent of prostaglandin-based therapy, such as epoprostenol (Flolan), heart and lung transplantation was the only option for severe disease. However, most patients died while waiting for an organ."
The PVD Clinic at UAB was established in 1988 by Robert C. Bourge, MD, in response to clinical needs in the southeastern United States. Since then, UAB's multifaceted program for patients with PAH has grown to include both an extensive clinical component and a research consortium designed to study and treat the disorder from the cellular level to the human clinical condition.
According to Bourge, the PVD Clinic has been one of the most active programs in the world in the last 5 years and includes, in addition to Bourge and Benza, cardiologists Barry K. Rayburn, MD, José A. Tallaj, MD, Laura J. Pinderski, MD, and Salpy V. Pamboukian, MD.
Incidence
Primary pulmonary hypertension (PPH), one of the most devastating causes of PAH, is a rare disease, with an estimated 300 new cases occurring annually in the US. Although etiology remains unknown, the genetics and potentially contributing environmental factors are now better understood.
PPH affects individuals of all ages, although the condition occurs more frequently in women aged 21 to 40 years. "An estimated 6% to 12% of PPH cases are familial and have an autosomal dominant pattern of inheritance with incomplete penetrance and genetic anticipation, which means the disease develops at an earlier age in each successive generation," notes Benza. "We now know that mutations in the bone morphogenetic protein receptor type II (BMPR2) account for 25% of inherited cases of PPH. Anorexigens, such as fenfluramine and dexfenfluramine, promote PAH in some individuals and have been linked to acquired mutations in the BMPR2 gene."
Disease Classification
The normal mean pulmonary artery pressure in adults is 14 mm Hg; in pulmonary hypertension, it is >25 mm Hg at rest and >30 mm Hg during exercise.
Until 1998, when the World Health Organization (WHO) sponsored an international symposium on pulmonary hypertension to refine disease classification, the disorder was characterized as either primary (idiopathic) or secondary.
The WHO classification divides the causes of pulmonary hypertension into five categories and groups disorders with similar characteristics, such as in situ thrombosis, smooth muscle hypertrophy, and intimal proliferation, into the new category PAH. "Distinctions in categories are important because PAH-specific therapies can potentially harm patients with other forms of pulmonary hypertension, particularly those related to left ventricular dysfunction or pulmonary veno-occlusive disease," says Benza.
PAH includes conditions in which the pulmonary arteries are the primary site of the pathology, such as PPH, as well as pulmonary hypertension resulting from congenital heart disease, connective tissue diseases (especially scleroderma), liver disease, and human immunodeficiency virus infections.
"Based on new knowledge of pulmonary vascular disease pathogenesis, the WHO reclassification is more inclusive, making it easier for clinicians to individualize treatment strategies," Benza says. "Additionally, the WHO symposium stressed functional assessments, including a modification of the New York Heart Association Functional Classification for heart disease, a 6-minute walk test, and hemodynamic assessments to guide and adjust therapy."
Complex Diagnosis
Diagnosis of PAH remains complex and many patients fail to report symptoms until normal activities are significantly impaired; average time between the initial appearance of symptoms and diagnosis is 3 years, according to National Institutes of Health data. Early symptoms include fatigue, dyspnea, and syncope during exercise; also common are edema, cyanosis, and angina. Patients with advanced disease generally can perform only minimal activities and often experience symptoms at rest.
"Transthoracic echocardiograms, serologic tests for collagen vascular diseases, pulmonary function tests, and perfusion lung scan can help differentiate between PAH and other forms of pulmonary hypertension. "Once PAH is identified, right heart catheterization, performed by a specialist, is essential for diagnostic confirmation," Benza says. Prompt referral to a specialized center is critical, as there is a significant risk of early death with advanced disease."
Aim of Treatment
Patients with pulmonary vascular disease must be followed closely and serially by experienced physicians, as failure to adjust treatment strategies can quickly lead to serious, and often fatal, consequences.
|
Current PAH treatments aim to prevent or reverse vasoconstriction, vascular remodeling, and thrombosis. Options include warfarin, calcium channel blockers (after appropriate vasodilator testing, as their use carries a significant risk of death if utilized indiscriminately), endothelin blockers such as bosentan (Tracleer), prostacyclin analogs including epoprostenol and treprostinol (Remodulin), and for patients refractory to medical therapy, atrial septostomy or consideration for lung or heart and lung transplantation.
"In PAH patients, studies have shown (Circ J Am Heart Assoc. 2002;106:1477-1482 and Am J Respir Crit Care Med. 2002;165:800-804) that prostaglandin therapy may improve survival, WHO functional class, and quality of life," Benza says. "However, these drugs are extremely expensive, have substantial adverse effects, and require expert care for safe administration."
Epoprostenol, a potent vasodilator that inhibits smooth muscle cell proliferation, must be delivered via an indwelling central venous catheter. It increases cardiac output and improves pulmonary vascular resistance but is associated with adverse reactions such as diarrhea, flushing, jaw pain, and a risk of fatal sepsis if the central catheter becomes infected. Fatal rebound pulmonary hypertension can occur if drug flow is interrupted.
Treprostinol has a longer half-life than epoprostenol and can be administered by subcutaneous injection. Unfortunately, it shares the prostacyclin-related complications of epoprostenol and has its own unique problems, including pain, erythema, and induration at the injection site.
Until the recent Food and Drug Administration (FDA) approval of bosentan, oral drug options for PAH were limited to long-term anticoagulant therapy or calcium channel blockers, which improve survival in a limited number of patients. A recent study (N Engl J Med. 2002;346: 896-903) found bosentan improved cardiopulmonary hemodynamics and WHO functional class, while increasing time to clinical worsening.
"Bosentan is a nonselective endothelin-1 (ET-1) receptor antagonist. High levels of ET-1, which induce vessel narrowing and vasoconstriction, are often found in PAH patients and are associated with disease severity," Benza says. "Although bosentan inhibits smooth muscle cell growth, it may also interfere with the action of favorable endothelin receptors in the kidney, which could promote generalized edema. In addition, bosentan therapy is associated with a 10% chance of worsening liver enzymes and requires frequent evaluation of liver function."
Experimental Therapy
To overcome limitations of current FDA-approved therapies for PAH, UAB PVD research physicians are investigating experimental treatments, including oral prostacyclins, more highly selective endothelin antagonists, sildenafil (Viagra), and novel combination therapies.
"Many patients remain severely symptomatic, despite prostacyclin-based treatment or experience intolerable side effects with their current therapy," reports Benza. "Using a combination of medications with different mechanisms of action could offer synergistic or additive effects in vascular remodeling and clinical status, and perhaps, allow reduction of individual doses to avoid toxic side effects."
A recent UAB study (Circ J Am Heart Assoc: submitted) found combination therapy with bosentan and either epoprostenol or treprostinol improved hemodynamics and WHO functional status. "Although the addition of bosentan proved effective, more adverse effects were reported than with bosentan alone," Benza says. "Further studies are needed to define optimal dosing strategies for combination therapy."
Ongoing research at the UAB PVD Clinic also includes evaluation of an implantable device for hemodynamic monitoring, which could reduce the need for right heart catheterizations, as well as novel pulmonary artery imaging techniques, such as intravascular ultrasound and magnetic resonance imaging.
"Although we offer new therapeutic options for our patients, both approved and experimental, our experience, and that of other pulmonary hypertension centers, emphasize it is extremely important that PVD patients be followed closely and serially by experienced physicians, as failure to adjust treatment strategies can quickly lead to serious, and often fatal, consequences" says Benza.
Basic Research
UAB's team of basic and translational investigators is using an integrative approach to uncover mechanisms of PAH pathogenesis and bring new therapies to fruition. "Our basic research includes a cell core, which is investigating endothelial and smooth muscle cell action; an animal core, studying in vivo regulation of factors that contribute to PAH; and a gene therapy core. This latter core is testing the efficacy of a novel viral vector in cells, animals, and eventually humans to mitigate or reverse pathologic remodeling of the pulmonary arteries," he says.
Enabled by the recent discovery of several functional proteins and genes involved in the genesis of PPH, the gene therapy core is utilizing an innovative technique developed at UAB. "By combining transductional and transcriptional targeting, we have developed a viral vector that binds specifically to pulmonary endothelial cells," explains UAB Gene Therapy Center Director David T. Curiel, MD, PhD. "The ability to selectively target the pulmonary endothelium, coupled with the knowledge of which genes to target, allows for therapeutic viral delivery, while reducing the potential for transgene-induced toxicity. Many diseases affect the pulmonary vasculature, and this novel technique will create treatment possibilities for a number of other conditions."
Benza concludes, "Breakthroughs in our understanding of PAH pathogenesis have opened exciting new research pathways that will ultimately lead to more effective treatments for patients with this devastating disease."
World Health Organization Functional Classification of Pulmonary Hypertension
| Class I – Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. |
Class III – Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.
|
| Class II – Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea |
Class IV – Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present even at rest. Discomfort is increased by any physical activity. |
For more information
Dr. Raymond Benza
1.800.UAB.MIST
mist@uabmc.edu
UAB Insight, Fall 2003