ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension

HomeCirculationVol. 119, No. 16ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBACCF/AHA 2009 Expert Consensus Document on Pulmonary HypertensionA Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: Developed in Collaboration With the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association Writing Committee Members Vallerie V. McLaughlin, MD, FACC, FAHA, FCCP, Chair, Stephen L. Archer, MD, FACC, FAHA, David B. Badesch, MD, FCCP, Robyn J. Barst, MD, FACC, FAHA, FCCP, Harrison W. Farber, MD, FAHA, FCCP, Jonathan R. Lindner, MD, FACC, Michael A. Mathier, MD, FACC, Michael D. McGoon, MD, FACC, FCCP, Myung H. Park, MD, FACC, Robert S. Rosenson, MD, FACC, FAHA, Lewis J. Rubin, MD, FAHA, FCCP, Victor F. Tapson, MD and John Varga, MD, FACR Writing Committee Members Search for more papers by this author , Vallerie V. McLaughlinVallerie V. McLaughlin Search for more papers by this author , Stephen L. ArcherStephen L. Archer Search for more papers by this author , David B. BadeschDavid B. Badesch Search for more papers by this author , Robyn J. BarstRobyn J. Barst Search for more papers by this author , Harrison W. FarberHarrison W. Farber Search for more papers by this author , Jonathan R. LindnerJonathan R. Lindner Search for more papers by this author , Michael A. MathierMichael A. Mathier Search for more papers by this author , Michael D. McGoonMichael D. McGoon Search for more papers by this author , Myung H. ParkMyung H. Park Search for more papers by this author , Robert S. RosensonRobert S. Rosenson Search for more papers by this author , Lewis J. RubinLewis J. Rubin Search for more papers by this author , Victor F. TapsonVictor F. Tapson Search for more papers by this author and John VargaJohn Varga Search for more papers by this author Originally published30 Mar 2009https://doi.org/10.1161/CIRCULATIONAHA.109.192230Circulation. 2009;119:2250–2294is corrected byCorrectionOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 30, 2009: Previous Version 1 Preamble…22521. Executive Summary…2252 1.1. Pathology and Pathogenesis…2252 1.2. Classification and Epidemiology…2253 1.3. Natural History and Survival…2253 1.4. Screening and Diagnostic Assessment…2253 1.5. Evidenced-Based Treatment Algorithm…2253 1.6. Reassessing Patients Over Time: How to Follow Patients on Treatment…2254 1.7. Non-Pulmonary Arterial Hypertension Pulmonary Hypertension Populations…2254 1.8. Pulmonary Arterial Hypertension in Congenital Heart Disease…2254 1.9. Pediatric Pulmonary Arterial Hypertension…22542. Introduction…22543. Pathology and Pathogenesis…2255 3.1. Histology…2255 3.2. The Right Ventricle…2255 3.3. Molecular Abnormalities in Pulmonary Arterial Hypertension…2255 3.4. Genetics of Pulmonary Arterial Hypertension…2255 3.5. Abnormalities in the Blood and Endothelium in Pulmonary Arterial Hypertension…2255 3.6. Prostacyclin and Thromboxane A2…2256 3.7. Endothelin-1…2256 3.8. Nitric Oxide…2256 3.9. Additional Vasoactive Substances…2256 3.10. Inflammation…2256 3.11. Pulmonary Artery Smooth Muscle Cells in Pulmonary Arterial Hypertension…22564. Classification and Epidemiology of Pulmonary Arterial Hypertension (WHO Group I)…2256 4.1. Idiopathic Pulmonary Arterial Hypertension…2256 4.2. Familial Pulmonary Arterial Hypertension…2256 4.3. Pulmonary Arterial Hypertension Associated With Congenital Heart Disease…2257 4.4. Pulmonary Arterial Hypertension Associated With Connective Tissue Diseases…2258 4.5. Pulmonary Arterial Hypertension Associated With Human Immunodeficiency Virus Infection…2258 4.6. Pulmonary Arterial Hypertension Associated With Portal Hypertension…2258 4.7. Pulmonary Arterial Hypertension Associated With Drugs and Toxins…2258 4.8. Pulmonary Arterial Hypertension Associated With Hemoglobinopathies…2258 4.9. Pulmonary Arterial Hypertension Associated With Other Etiologies…2258 4.10. Pulmonary Arterial Hypertension Associated With Pulmonary Venous or Capillary Abnormalities…22595. Natural History and Survival…2259 5.1. Medical Therapy for Pulmonary Arterial Hypertension: Impact Upon Survival…2259 5.2. Factors Impacting Survival and Facilitating Assessment of Prognosis…2260 5.3. Functional Class…2260 5.4. Exercise Tolerance…2260 5.5. Hemodynamics…2260 5.6. Echocardiography…2260 5.7. Magnetic Resonance Imaging…2260 5.8. Biomarkers…2261 5.9. Summary of Recommendations…22616. Screening and Diagnostic and Hemodynamic Assessment…2261 6.1. Definition of Pulmonary Hypertension…2261 6.2. Diagnostic Strategy…2261 6.3. Echocardiography…2262 6.4. Exercise Echocardiography…2263 6.5. Newer Imaging Techniques in the Diagnostic Assessment of Pulmonary Hypertension…2263 6.6. Invasive Hemodynamic Assessment…2264 6.7. Right Heart Catheterization…2266 6.8. Components of an Optimal Invasive Evaluation…2266 6.9. Safety of Heart Catheterization…2267 6.10. Spontaneous Variability in Pulmonary Artery Pressure…2267 6.11. Ambulatory Measurement of Pulmonary Hemodynamics…2267 6.12. Acute Vasodilator Testing…2267 6.13. Agents for Acute Vasodilator Testing…2267 6.14. Definition of Responders to Acute Vasodilator Testing in Pulmonary Arterial Hypertension…2268 6.15. Vasodilator Testing in Pulmonary Arterial Hypertension Subsets…2268 6.16. Summary…22687. Evidence-Based Treatment Algorithm…2268 7.1. General Measures…2269 7.2. Background Therapy…2269 7.3. Calcium Channel Blockers…2269 7.4. Prostanoids…2270 7.5. Epoprostenol…2270 7.6. Treprostinil…2270 7.7. Iloprost…2271 7.8. Endothelin Receptor Antagonists…2271 7.9. Bosentan…2271 7.10. Sitaxsentan…2272 7.11. Ambrisentan…2272 7.12. Phosphodiesterase Inhibitors…2272 7.13. Sildenafil…2273 7.14. Tadalafil…2273 7.15. Combination Therapy…2273 7.16. Limitations of Clinical Trials in Pulmonary Arterial Hypertension…2273 7.17. Cost Considerations…2274 7.18. Invasive Therapies…2274 7.19. Atrial Septostomy…2274 7.20. Lung and Combined Heart and Lung Transplantation…2274 7.21. Pulmonary Thromboendarterectomy…2275 7.22. Right Ventricular Assist Device…2275 7.23. Treatment Algorithm…22758. Reassessing Patients Over Time: How To Follow Patients on Treatment…2275 8.1. Role of Nurses in Managing Pulmonary Arterial Hypertension Patients at Specialty Centers…22759. Non-Pulmonary Arterial Hypertension Pulmonary Hypertension Populations…2276 9.1. WHO Group 2: Pulmonary Venous Hypertension…2277 9.1.1. Systolic Heart Failure and Pulmonary Hypertension…2277 9.1.2. Diastolic Heart Failure and Pulmonary Hypertension…2278 9.1.3. Valvular Dysfunction and Pulmonary Hypertension…2279 9.2. WHO Group 3: Hypoxia-Associated Pulmonary Hypertension…2279 9.2.1. Chronic Obstructive Pulmonary Disease and Pulmonary Hypertension…2279 9.2.2. Interstitial Lung Disease and Pulmonary Hypertension…2279 9.2.3. Sleep Disordered Breathing…2280 9.3. WHO Group 4: Thromboembolic Pulmonary Hypertension…2280 9.3.1. Surgical and Invasive Therapy…2280 9.3.2. Medical Therapy…2280 9.3.3. Pulmonary Hypertension in the Cardiac Surgical Patient…2281 9.3.4. Preoperative Pulmonary Hypertension…2281 9.3.5. Postoperative Pulmonary Hypertension…2281 9.4. Summary of Recommendations…228110. Congenital Heart Disease-Related Pulmonary Arterial Hypertension…228211. Pediatric Pulmonary Arterial Hypertension…2283 11.1. Persistent Pulmonary Hypertension of the Newborn…2283 11.2. Pediatric Pulmonary Arterial Hypertension…228312. Pulmonary Hypertension Centers of Excellence…2284References…2284Appendix 1. Author Relationships With Industry and Other Entities…2290Appendix 2. Peer Reviewer Relationships With Industry and Other Entities…2292PreambleThis document has been developed by the American College of Cardiology Foundation (ACCF) Task Force on Expert Consensus Documents (ECDs), and was cosponsored by the American Heart Association (AHA). Expert Consensus Documents are intended to inform practitioners and other interested parties of the opinion of the ACCF and cosponsors concerning evolving areas of clinical practice and/or technologies that are widely available or new to the practice community. Topics chosen for coverage by expert consensus documents are so designed because the evidence base, the experience with technology, and/or the clinical practice are not considered sufficiently well developed to be evaluated by the formal American College of Cardiology Foundation (ACCF)/AHA practice guidelines process. Often the topic is the subject of ongoing investigation. Thus, the reader should view the ECD as the best attempt of the ACCF and the cosponsors to inform and guide clinical practice in areas where rigorous evidence may not be available or the evidence to date is not widely accepted. When feasible, ECDs include indications or contraindications. Some topics covered by ECDs will be addressed subsequently by the ACCF/AHA Practice Guidelines Committee.Because the development of expert consensus documents depends on the knowledge and experience of experts and investigators in the field, many of whom have relationships with industry (RWI), the policy addressing writing committee members’ RWI must be realistic, workable, and implemented in a way that protects the integrity of the process while allowing an open and honest exchange of the most up-to-date information. Every possible effort is made to formulate a writing committee with a reasonable balance of RWI. Specifically, all members of the writing panel are asked to provide disclosure statements of all relationships that might be perceived as real or potential conflicts of interest. Participation in the writing committee is dependent on a review of all relevant RWI by the task force to ensure balance so that fair and unbiased consensus can be reached. In addition, statements of RWI are reported orally and in writing to all members of the writing panel at every meeting and conference call and are updated as changes occur.In the case of pulmonary hypertension, because of the relatively small number of experts engaged in clinical care and research in this area, identifying experts without RWI in this disease area was a challenge. To mitigate this concern and reduce the risk of bias, extensive peer review was completed in addition to review and approval by the AHA’s Scientific Advisory Coordinating Committee (SACC) and the ACCF’s Board of Trustees. SACC members only participate in the review and approval process if they have no relevant RWI themselves. To provide complete transparency, the RWI information for writing committee members and peer reviewers are published in the appendixes of the document.Robert A. Harrington, MD, FACC Chair, ACCF Task Force on Expert Consensus Documents1. Executive SummaryPulmonary hypertension (PH) is a complex, multidisciplinary disorder. Recent advances have led to increased recognition and new therapies. While some data exist to form treatment guidelines, other areas have been inadequately explored.1.1. Pathology and PathogenesisPulmonary arterial hypertension (PAH) is a syndrome resulting from restricted flow through the pulmonary arterial circulation resulting in increased pulmonary vascular resistance and ultimately in right heart failure. Multiple pathogenic pathways have been implicated in the development of PAH, including those at the molecular and genetic levels and in the smooth muscle and endothelial cells and adventitia. The imbalance in the vasoconstrictor/vasodilator milieu has served as the basis for current medical therapies, although increasingly it is recognized that PAH also involves an imbalance of proliferation and apoptosis (favoring the former).1.2. Classification and EpidemiologyWhile previously considered a rare disease, the most recent evidence from a French registry suggests that the prevalence of PAH is about 15 per million.1 Idiopathic pulmonary arterial hypertension (IPAH) is more prevalent in women and was the most common type of PAH in the French registry. Familial PAH often results from a mutation in the bone morphogenic protein receptor-2 (BMPR2) and is inherited as an autosomal dominant disease with incomplete penetrance and genetic anticipation. PAH is also associated with congenital heart disease (CHD), connective tissue diseases, drugs and toxins, human immunodeficiency virus (HIV), portal hypertension, hemoglobinopathies, and myeloproliferative disorders. Primary PH formerly encompassed idiopathic, familial, and anorexigen induced PAH. These groups together comprise World Health Organization (WHO) Group I PAH. Other WHO categories include Group II, PH with left heart disease, Group III, PH associated with lung diseases and/or hypoxemia, Group IV, PH due to chronic thrombotic and/or embolic disease, and Group V, miscellaneous causes of PH (Table 1). Table 1. Revised WHO Classification of PHReprinted from Simonneau et al.321. Pulmonary arterial hypertension (PAH) 1.1. Idiopathic (IPAH) 1.2. Familial (FPAH) 1.3. Associated with (APAH): 1.3.1. Connective tissue disorder 1.3.2. Congenital systemic-to-pulmonary shunts 1.3.3. Portal hypertension 1.3.4. HIV infection 1.3.5. Drugs and toxins 1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, chronic myeloproliferative disorders, splenectomy) 1.4. Associated with significant venous or capillary involvement 1.4.1. Pulmonary veno-occlusive disease (PVOD) 1.4.2. Pulmonary capillary hemangiomatosis (PCH) 1.5. Persistent pulmonary hypertension of the newborn2. Pulmonary hypertension with left heart disease 2.1. Left-sided atrial or ventricular heart disease 2.2. Left-sided valvular heart disease3. Pulmonary hypertension associated with lung diseases and/or hypoxemia 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Sleep disordered breathing 3.4. Alveolar hypoventilation disorders 3.5. Chronic exposure to high altitude 3.6. Developmental abnormalities4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease (CTEPH) 4.1. Thromboembolic obstruction of proximal pulmonary arteries 4.2. Thromboembolic obstruction of distal pulmonary arteries 4.3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign material)5. Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)1.3. Natural History and SurvivalThe prognosis of PAH is poor, with an approximately 15% mortality within 1 year on modern therapy.2 Predictors of a poor prognosis include: advanced functional class, poor exercise capacity as measured by 6-minute walk (6MW) test or cardiopulmonary exercise test, high right atrial (RA) pressure, significant right ventricular (RV) dysfunction, evidence of RV failure, low cardiac index, elevated brain natriuretic peptide (BNP), and underlying diagnosis of scleroderma spectrum of diseases.1.4. Screening and Diagnostic AssessmentPatients at sufficient risk for the development of PAH to warrant periodic screening include those with a known BMPR2 mutation, scleroderma spectrum of diseases, and portal hypertension who are undergoing evaluation for liver transplantation. The most appropriate study to obtain in patients suspected of having PH based on history, physical examination, chest x-ray (CXR), and electrocardiogram (ECG) is an echocardiogram. Evaluation for other potential etiologies, such as thromboembolic disease, is appropriate in all patients suspected of having PAH. The diagnosis of PAH requires confirmation with a complete right heart catheterization (RHC). The current hemodynamic definition of PAH is a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg; a pulmonary capillary wedge pressure (PCWP), left atrial pressure, or left ventricular end-diastolic pressure (LVEDP) less than or equal to 15 mm Hg; and a pulmonary vascular resistance (PVR) greater than 3 Wood units.3 Acute vasodilator testing, which involves the administration of pharmacologic agents to test the presence of pulmonary vasoreactivity, has prognositic value and should be performed in all IPAH patients who might be considered potential candidates for long-term calcium-channel blocker therapy. Those with overt right heart failure or hemodynamic instability should not undergo acute vasodilator testing. The definition of an acute responder is a reduction in mPAP of at least 10 mm Hg to an absolute mPAP of less than 40 mm Hg without a decrease in cardiac output. Vasodilator testing should be performed by centers with experience in the administration of these agents and the interpretation of the results.1.5. Evidenced-Based Treatment AlgorithmGoals of treatment include improvement in the patient’s symptoms, quality of life, and survival. Objective assessments to measure treatment response include improvement in exercise capacity (6MW test, cardiopulmonary exercise test, treadmill test), hemodynamics, and survival. General measures that should be addressed include diet, exercise, appropriate vaccinations, and avoidance of pregnancy. Warfarin anticoagulation is recommended in all patients with IPAH based on 1 prospective and 2 retrospective observational, uncontrolled trials. Diuretics are used for symptomatic management of RV volume overload. Oxygen is recommended to maintain oxygen saturation greater than 90%. Calcium channel blockers are indicated only for patients who have a positive acute vasodilator response as described in the preceding text. Patients treated with calcium channel blockers should be followed closely for both the safety and the efficacy of this therapy. Continuous intravenous epoprostenol improves exercise capacity, hemodynamics, and survival in IPAH and is the preferred treatment option for the most critically ill patients. Although expensive and cumbersome to administer, epoprostenol is the only therapy for PAH that has been shown to prolong survival. Treprostinil, a prostanoid, may be delivered via either continuous intravenous or subcutaneous infusion. Iloprost is a prostanoid delivered by an adaptive aerosolized device 6 times daily. The delivery system and side effects of the prostanoids should be carefully considered when assessing patients for prostanoid therapy. The endothelin receptor antagonists are oral therapies that improve exercise capacity in PAH. Liver function tests must be monitored indefinitely on a monthly basis. Phosphodiesterase (PDE)-5 inhibitors also improve exercise capacity and hemodynamics in PAH. In general, patients with poor prognostic indexes should be initiated on parenteral therapy, while patients with class II or early III symptoms commonly commence therapy with either endothelin receptor antagonists or PDE-5 inhibitors. Given the multiple mechanisms of action, there is scientific rationale for the use of combination therapy for PAH, which is an area of active investigation. Initial results are encouraging and more combination therapy trials are underway. Lung transplantation is an option for selected patients who progress despite optimal medical management.1.6. Reassessing Patients Over Time: How to Follow Patients on TreatmentDue to the complex nature of the disease and its treatments, PAH patients must be closely followed. In general, office visits should be more frequent for patients with advanced symptoms, right heart failure, and advanced hemodynamics and those on parenteral or combination therapy. Such patients generally should be seen every 3 months (or more frequently). Less ill patients on oral therapy generally should be seen every 3 to 6 months. Most experts obtain an assessment of functional class and exercise capacity, such as a 6MW or graded treadmill test, with each office visit. Nurse clinicians experienced in the care of PAH patients should be an integral part of chronic outpatient management.1.7. Non-Pulmonary Arterial Hypertension Pulmonary Hypertension PopulationsMost cardiologists and pulmonologists will see PH associated with elevated left heart filling pressures much more frequently than PAH. Any disorder that elevates left heart filling pressures, including systolic dysfunction, diastolic dysfunction, and valvular heart disease, can result in elevated pulmonary artery pressures. Treatment should be directed at the underlying left heart disease. In rare instances, PAH-specific therapy may be considered if the underlying cause has been optimally treated, the PCWP is normal or minimally elevated, the transpulmonary gradient and pulmonary vascular resistance are significantly elevated, and the patient’s symptoms suggest that PAH-specific therapy may yield clinical benefit. This subset of patients may be described as those with “disproportionate” PH (greater than expected on the basis of their elevated left heart pressure or lung disease). Experts caution against widespread treatment for non-PAH PH until clinical trial data indicate whether such patients benefit from them. The potential adverse effects of PAH-specific therapies in such patients include worsening fluid retention, pulmonary edema, and ventilation perfusion mismatch.1.8. Pulmonary Arterial Hypertension in Congenital Heart DiseaseThe incidence of CHD is approximately 8 per 1000 live births,4 and approximately 30% of children who do not undergo surgical repair will develop pulmonary vascular disease. Patients with PAH related to CHD who are not candidates for surgical correction are treated similar to IPAH patients. The natural history of such patients tends to be better than those with other types of PAH.1.9. Pediatric Pulmonary Arterial HypertensionPersistent PH of the newborn is a syndrome characterized by increased pulmonary vascular resistance, right to left shunting, and severe hypoxemia. Treatment options include inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation. Pediatric IPAH is treated similar to that in adults. A higher percentage of children are acute responders and candidates for calcium channel blockers.2. IntroductionThe field of PH has evolved substantially over the past decade. While there are some data from which evidence based guidelines for PAH have been generated, other aspects of the assessment and management of PH have been largely unexplored.The writing committee consisted of acknowledged experts in the field of PH. In addition to members designated by the ACCF and AHA, the writing committee included representation from the American College of Chest Physicians (ACCP); the American College of Rheumatology; the American Thoracic Society, Inc. (ATS); and the Pulmonary Hypertension Association (PHA). This diverse representation reflects the multidisciplinary nature of PH. Representation by an outside organization does not necessarily imply endorsement. This document was reviewed by 4 official representatives from the ACCF and AHA; organizational review by the ACCP, ATS, and PHA; as well as by 13 content reviewers. This document was approved for publication by the governing bodies of the ACCF in November 2008 and AHA in February 2009. In addition, the governing boards of the ACCP, ATS, and PHA formally endorsed this document. This document will be considered current until the Task Force on ECDs revises it or withdraws it from publication.This statement is the first ACCF/AHA Clinical Expert Consensus Document on PH. At its first meeting, each member of this ACCF/AHA writing committee indicated any relationships with industry, and these relationships were reiterated at each subsequent meeting and on each conference call. Relevant conflicts of the writing committee and peer reviewers are reported in Appendixes 1 and 2, respectively. At the first meeting, the writing committee discussed the topics to be covered in the document and assigned lead authors for each section. The entire writing group reviewed each section and discussed important issues for further drafts. The committee met again to come to a consensus on outstanding issues, and further meetings and teleconferences occurred between the chairman and writing group members who were not present at the meetings to ensure consensus on important points. In instances where there was not consensus amongst the writing group, a majority opinion and a minority opinion is presented. Each writing group member has read and approved the entire document. Outside peer review was also undertaken before the document was finalized.3. Pathology and PathogenesisPAH is a syndrome resulting from restricted flow through the pulmonary arterial circulation, which leads to pathological increases in PVR and ultimately to right heart failure.5 The predominant cause of increased PVR is loss of vascular luminal cross section due to vascular remodeling produced by excessive cell proliferation and reduced rates of apoptosis, although excessive vasoconstriction plays a significant role in approximately 20% of patients.6,7Improved understanding of the disease pathways in PAH, even if a single primary cause remains elusive, has led to therapeutic strategies, including the administration of prostanoids, the antagonism of endothelin receptors, and inhibition of PDE-5. Future therapeutic options identified by basic studies include inhibiting pyruvate dehydrogenase kinase (PDK), the serotonin transporter (5-HTT), the antiapoptotic protein survivin, several transcription factors (notably hypoxia inducible factor-1 alpha [HIF-1 alpha] nuclear factor activating T lymphocytes [NFAT]), and augmenting voltage-gated potassium channel channels (e.g., Kv1.5). Additional therapies in early clinical development include vasoactive intestinal peptide and tyrosine kinase inhibitors. Administration of angiogenic factors and stem cells and agents targeting mitochondrial dysfunction may also have therapeutic promise.3.1. HistologyPAH is a panvasculopathy predominantly affecting small pulmonary arteries (also called “resistance arteries” because they regulate regional blood flow in the lung).8 PAH is characterized by a variety of arterial abnormalities, including intimal hyperplasia, medial hypertrophy, adventitial proliferation, thrombosis in situ, varying degrees of inflammation, and plexiform arteriopathy. An individual patient may manifest all of these lesions, and the distribution of lesions may be diffuse or focal. Our understanding of the natural history of the evolution of vascular lesions in PAH, except for patients with CHD, is limited because biopsies are rarely obtained in adult patients. However, it is believed that medial hypertrophy is an earlier and more reversible lesion than intimal fibrosis or plexogenic arteriopathy.3.2. The Right VentricleRV function is a major determinant of functional capacity and prognosis in PAH.5 While RV hypertrophy and dilatation are initiated by increased afterload (i.e., elevated PVR), the adequacy of the RV’s compensatory response (preservation of stroke volume) is quite variable amongst individuals. It remains unclear why some RVs compensate while others decompensate, manifest as thinning and dilatation of the wall, and reduce the RV ejection fraction. The neonatal RV is much more tolerant of increased PVR, partially explaining the better survival in children with PAH associated with CHD. RV function could potentially be improved by effective therapies to regress pulmonary vascular obstruction or by directly improving RV contractile function.3.3. Molecular Abnormalities in Pulmonary Arterial HypertensionThe pathobiological mechanisms of PAH have recently been reviewed.9 The PAH “phenotype” is characterized by endothelial dysfunction, a decreased ratio of apoptosis/proliferation in pulmonary artery smooth muscle cells (PASMCs), and a thickened, disordered adventitia in which there is excessive activation of adventitial metalloproteases. Like cancer and atherosclerosis, PAH does not have a single cause: a “multi-hit model” is more likely.3.4. Genetics of Pulmonary Arterial HypertensionPAH is inherited in less than 10% of cases).1,10 Mutations in 2 genes in the transforming growth factor beta receptor pathway, BMPR2, and activin-like kinase 1 have been implicated in the pathogenesis of familial PAH. BMPR2 modulates vascular cell growth by activating the intracellular pathways of SMAD and LIM kinase.11–13 Many different BMPR2 mutations occur in familial PAH. These mutations, which lead to loss of function in the SMAD signaling pathway, are prevalent in familial PAH (prevalence ∼75%).11,12 Activin-like kinase 1 mutations, detected in a group of patients with hereditary hemorrhagic telangiectasia and PAH,13 are also thought to result in growth-promoting alterations of SMAD-dependent signaling. Overexpression of a dominant negative form of BMPR2 in PASMC leads to PAH and Kv1.5 downregulation in transgenic mice.14,153.5. Abnormalities in the Blood and Endothelium in Pulmonary Arterial HypertensionIn the vascular lumen, PAH is characterized by platelets that are depleted of serotonin and elevation of plasma serotonin.16 Endothelial dysfunction is common in PAH. The PAH endothelium is characterized by increased production of vasoconstrictor/mitogenic compounds, such as endothelin and thromboxane, and deficient production of vasodilators, such as prostacyclin.17–19 Elevated levels of fibrinopep