{"product_id":"pulmonary-arterial-hypertension-a-comprehensive-guide-for-patients","title":"Pulmonary Arterial Hypertension: A Comprehensive Guide for Patients","description":"\u003cp\u003ePulmonary arterial hypertension (PAH) is a rare but serious condition. In PAH, the blood vessels of the lungs become narrowed and stiff. This forces the right side of the heart to work much harder than normal. This review article summarizes how PAH is defined, classified, diagnosed, and treated, drawing on decades of research. The article explains that PAH is one of five groups of pulmonary hypertension. PAH affects roughly 25 people per million in Western countries. PAH is driven by genetic mutations in about 80% of inherited cases. Without treatment, PAH leads to right heart failure and death. Targeted treatments developed over the past two decades have reduced hospitalizations in clinical trials, though the most recent large trials of combined oral treatment have not shown a clear effect on survival.\u003c\/p\u003e\n\n\u003ch1\u003ePulmonary Arterial Hypertension: A Comprehensive Guide for Patients\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eWhat Is Pulmonary Arterial Hypertension?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#history\"\u003eHow Our Understanding Has Evolved\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#classification\"\u003eThe Five Groups of Pulmonary Hypertension\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#global\"\u003eA Global Health Problem\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#pathology\"\u003eWhat Happens Inside the Blood Vessels\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#right-ventricle\"\u003eThe Right Ventricle: The Key to Survival\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#genetics\"\u003eGenetic Features of PAH\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#clinical\"\u003eClinical Presentation and Diagnosis\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#treatment\"\u003eTreatment Approaches\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#implications\"\u003eWhat This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations and Unanswered Questions\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003ePAH is a rare condition where lung blood vessels narrow and stiffen, forcing the right heart to work harder; without treatment, it leads to right heart failure and death.\u003c\/li\u003e\n\u003cli\u003eRight heart catheterization is the gold standard for diagnosis, measuring mean pulmonary arterial pressure and pulmonary artery wedge pressure directly, and calculating pulmonary vascular resistance from these and cardiac output.\u003c\/li\u003e\n\u003cli\u003eTargeted treatments, including phosphodiesterase inhibitors and endothelin receptor antagonists, have been developed over the past two decades and have reduced hospitalizations in clinical trials, though the most recent large trials of combined treatment have not shown a clear effect on survival.\u003c\/li\u003e\n\u003cli\u003eRight ventricular function is the major determinant of survival; regular echocardiography or cardiac MRI can help track it.\u003c\/li\u003e\n\u003cli\u003eGenetic testing may be appropriate for patients with a family history of PAH or hereditary hemorrhagic telangiectasia to guide screening for family members.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eWhat Is Pulmonary Arterial Hypertension?\u003c\/h2\u003e\n\n\u003cp\u003ePulmonary hypertension is a syndrome characterized by marked remodeling of the pulmonary vasculature (the blood vessels in the lungs) and a progressive rise in the pulmonary vascular load. This means the blood vessels in the lungs become thick, narrow, and stiff over time. As a result, the right ventricle (the lower right chamber of the heart) must work harder to pump blood through the lungs.\u003c\/p\u003e\n\n\u003cp\u003eThis increased workload leads to hypertrophy (enlargement) and remodeling of the right ventricle. If pulmonary hypertension is left untreated, death results from right ventricular failure. The heart simply cannot keep up with the demand.\u003c\/p\u003e\n\n\u003cp\u003ePulmonary hypertension is currently defined hemodynamically (by blood flow measurements) as a mean pulmonary arterial pressure of higher than 20 mm Hg at rest. This measurement is taken by right heart catheterization, a procedure in which a thin tube is threaded through the heart to measure pressures directly.\u003c\/p\u003e\n\n\u003cp\u003eThere are two main types of pulmonary hypertension based on where the problem originates:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePrecapillary pulmonary hypertension\u003c\/strong\u003e — caused by disease in the pulmonary blood vessels themselves. This is defined by an elevation in pulmonary vascular resistance (PVR) of at least 3 Wood units (WU).\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eIsolated postcapillary pulmonary hypertension\u003c\/strong\u003e — caused by elevated filling pressures on the left side of the heart. In this type, PVR is less than 3 WU.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThis review focuses on the relatively rare form called pulmonary arterial hypertension (group 1). Immense progress has been achieved in understanding the mechanisms, natural history, and genetic features of PAH. Targeted therapy is now available for this condition.\u003c\/p\u003e\n\n\u003cp\u003eA full appreciation of the pathophysiology (how the disease develops and progresses) is important. The diagnosis requires a thorough clinical investigation to rule out other, more common forms of pulmonary hypertension. For those other forms, treatment of the underlying disease should be the primary goal.\u003c\/p\u003e\n\n\u003ch2 id=\"history\"\u003eHow Our Understanding Has Evolved\u003c\/h2\u003e\n\n\u003cp\u003eThe first anatomical description of pulmonary hypertension is credited to von Romberg. However, it was the advent of human right heart catheterization that truly opened the door to understanding this disease. Forssmann first performed the procedure on himself in 1929.\u003c\/p\u003e\n\n\u003cp\u003eThis led to a flurry of physiological observations on the heart and pulmonary circulation by Cournand and Richards in the 1940s. The three investigators received the Nobel Prize in Physiology or Medicine in 1956 for their seminal work. In his Nobel Lecture, Richards noted that as a result of their collective work, \"many forms and degrees of failure were defined, and their responses to treatment measured.\"\u003c\/p\u003e\n\n\u003cp\u003eIn 1951, Dresdale, a disciple of Cournand and Richards, and colleagues presented the first case series of patients with pulmonary hypertension of unknown cause. They defined this as \"primary pulmonary hypertension.\"\u003c\/p\u003e\n\n\u003cp\u003eGreater awareness of the disease developed in the 1960s after an epidemic of primary pulmonary hypertension associated with the use of the appetite suppressant aminorex. This prompted the World Health Organization to convene a first meeting of pulmonary hypertension experts in 1973. The goal was to standardize the clinical and pathological nomenclature of primary pulmonary hypertension. This was the first attempt at an organized classification.\u003c\/p\u003e\n\n\u003cp\u003eThe first and second meetings about pulmonary hypertension were separated by 25 years. Thereafter, the World Symposium on Pulmonary Hypertension (WSPH) was convened every 5 years. These meetings brought further refinement to the classification of pulmonary hypertension, with five distinct groups based on similar clinical and pathological findings and treatment responses.\u003c\/p\u003e\n\n\u003cp\u003eIdiopathic pulmonary arterial hypertension has replaced the term primary pulmonary hypertension. This change recognizes the hemodynamic and clinical similarities to other conditions that directly affect the pulmonary arterial vasculature and for which targeted therapy is available.\u003c\/p\u003e\n\n\u003cp\u003eThe recognition that some persons have a genetic predisposition to the disorder (familial pulmonary arterial hypertension) led to a landmark discovery. That discovery was mutations in the gene encoding bone morphogenetic protein (BMP) receptor type 2 (BMPR2). Since 80% of cases of familial pulmonary arterial hypertension and up to 20% of sporadic cases have germline BMPR2 mutations, the term was changed. The term familial pulmonary arterial hypertension was subsequently changed to heritable pulmonary arterial hypertension.\u003c\/p\u003e\n\n\u003cp\u003eIn the first two decades of this century, a flurry of novel oral, injectable, and inhaled drugs emerged. This was prompted by a growing interest in and understanding of pulmonary arterial hypertension. The development of these drugs followed and was based on various well-conducted, placebo-controlled studies.\u003c\/p\u003e\n\n\u003ch2 id=\"classification\"\u003eThe Five Groups of Pulmonary Hypertension\u003c\/h2\u003e\n\n\u003cp\u003eThe several forms of pulmonary hypertension are categorized into five clinical groups. This classification is based on the 2018 meeting of the World Symposium on Pulmonary Hypertension.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eGroup 1: Pulmonary Arterial Hypertension (PAH)\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cp\u003eThis group includes several subcategories:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e1.1 Idiopathic PAH\u003c\/li\u003e\n  \u003cli\u003e1.2 Heritable PAH\u003c\/li\u003e\n  \u003cli\u003e1.3 Drug- and toxin-induced PAH\u003c\/li\u003e\n  \u003cli\u003e1.4 PAH associated with connective-tissue disease, HIV infection, portal hypertension, congenital heart disease, or schistosomiasis\u003c\/li\u003e\n  \u003cli\u003e1.5 PAH long-term responders to calcium-channel blockers\u003c\/li\u003e\n  \u003cli\u003e1.6 PAH with overt features of venous or capillary involvement (PVOD or PCH)\u003c\/li\u003e\n  \u003cli\u003e1.7 Persistent PH of the newborn\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eClinical characteristics of group 1 include symptoms and signs of PAH. These include exertional dyspnea (shortness of breath with activity), syncope (fainting), elevated jugular-vein pressure, and pedal edema (swelling in the feet and ankles). Patients may also have signs of connective tissue disease, HIV infection, or liver disease. Echocardiographic signs are limited to right heart chambers. Other features may include a history of substance abuse (e.g., methamphetamines), exposure to drugs or toxins (e.g., fenfluramine, dexfenfluramine, dasatinib), or family history.\u003c\/p\u003e\n\n\u003cp\u003eThe hemodynamic profile for group 1 is precapillary PH: mPAP \u0026gt;20 mm Hg, PAWP ≤15 mm Hg, and PVR ≥3 WU.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eGroup 2: PH Due to Left-Sided Heart Disease\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cp\u003eSubcategories include PH due to heart failure with preserved LVEF and PH due to heart failure with reduced LVEF. Subcategories also include valvular heart disease and congenital or acquired cardiovascular conditions leading to postcapillary PH.\u003c\/p\u003e\n\n\u003cp\u003eClinical characteristics include symptoms and signs of left-sided or valvular heart disease. Echocardiographic signs show left-sided or valvular heart disease in addition to right-sided heart signs.\u003c\/p\u003e\n\n\u003cp\u003eThe hemodynamic profile can be isolated postcapillary PH (mPAP \u0026gt;20 mm Hg, PAWP \u0026gt;15 mm Hg, PVR \u0026lt;3 WU) or combined precapillary and postcapillary PH (mPAP \u0026gt;20 mm Hg, PAWP \u0026gt;15 mm Hg, PVR ≥3 WU).\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eGroup 3: PH Due to Lung Disease, Hypoxia, or Both\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cp\u003eSubcategories include obstructive lung disease, restrictive lung disease, other lung disease with mixed restrictive-obstructive pattern, hypoxia without lung disease, and developmental lung disorders.\u003c\/p\u003e\n\n\u003cp\u003eThe predominant clinical feature is chronic hypoxia at rest or with exercise. Patients have abnormal pulmonary-function tests and chest imaging, as well as abnormal polysomnogram (sleep study).\u003c\/p\u003e\n\n\u003cp\u003eThe hemodynamic profile is precapillary PH unless associated with a coexisting condition such as left-sided heart disease.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eGroup 4: PH Due to Pulmonary-Artery Obstructions\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cp\u003eSubcategories include chronic thromboembolic PH and other pulmonary-artery obstructions.\u003c\/p\u003e\n\n\u003cp\u003eClinical characteristics include symptoms and signs of PH, abnormal ventilation-perfusion scan, computed tomographic angiography, or both, and cancer. The hemodynamic profile is precapillary PH unless associated with a coexisting condition such as left-sided heart disease.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eGroup 5: PH with Multifactorial or Unclear Mechanisms\u003c\/strong\u003e\u003c\/p\u003e\n\n\u003cp\u003eSubcategories include hematologic disorders and systemic and metabolic disorders. Systemic and metabolic disorders include pulmonary Langerhans-cell histiocytosis, Gaucher's disease, glycogen storage disease, neurofibromatosis, and sarcoidosis. Others include chronic renal failure with or without hemodialysis and fibrosing mediastinitis. Complex congenital heart disease is also included.\u003c\/p\u003e\n\n\u003cp\u003eClinical characteristics include symptoms and signs of underlying disease (e.g., anemia, metabolic disorders). The hemodynamic profile can be precapillary PH (e.g., hemoglobinopathies or myeloproliferative disease) or isolated postcapillary PH or combined precapillary and postcapillary PH.\u003c\/p\u003e\n\n\u003ch2 id=\"global\"\u003eA Global Health Problem\u003c\/h2\u003e\n\n\u003cp\u003eThe prevalence of pulmonary hypertension varies according to the WSPH group classification. Pulmonary arterial hypertension (group 1) affects 25 persons per 1 million population in Western countries, with an annual incidence of 2 to 5 cases per million. Most of these patients are women.\u003c\/p\u003e\n\n\u003cp\u003eThe disease is most severe in elderly men, although it is less common in this population. Elderly men are more likely to have group 2 disease.\u003c\/p\u003e\n\n\u003cp\u003eFor other groups in the pulmonary hypertension classification, the prevalence varies according to the cause and disease state. However, the prevalence is likely to be greatly underestimated worldwide.\u003c\/p\u003e\n\n\u003cp\u003eMany widespread diseases of the cardiopulmonary systems are complicated by pulmonary hypertension, which greatly increases morbidity and mortality. Owing to the high prevalence of congenital heart diseases worldwide, particularly in developing countries, an estimate has been made. It is estimated that there are 25 cases of congenital heart disease-associated pulmonary arterial hypertension per 1 million population worldwide.\u003c\/p\u003e\n\n\u003cp\u003eValvular and left-sided heart disease are much more common. More than 100 million persons may have pulmonary hypertension due to left-sided heart disease (group 2) worldwide.\u003c\/p\u003e\n\n\u003cp\u003eSimilarly, pulmonary hypertension complicates chronic lung diseases. Chronic obstructive pulmonary disease (COPD) has a worldwide burden of more than 500 million cases. Interstitial lung disease has an estimated incidence of 10 to 70%. The prevalence of pulmonary hypertension is increased among patients with advanced disease.\u003c\/p\u003e\n\n\u003cp\u003eIn addition, more than 140 million persons live at high altitude (above 2500 m). However, the prevalence of pulmonary hypertension due to chronic hypoxia among persons living in high-altitude areas or persons relocating to such areas is unclear.\u003c\/p\u003e\n\n\u003cp\u003eFurthermore, pulmonary hypertension complicates highly prevalent viral infections (e.g., human immunodeficiency virus [HIV] infection) and parasitic diseases (e.g., schistosomiasis). It also complicates hemoglobinopathies such as sickle cell disease and thalassemia. Therefore, very large numbers of patients are affected in low- and middle-income areas of Africa, Asia, and South and Central America.\u003c\/p\u003e\n\n\u003cp\u003eThus, it is estimated that 1% of the world population and up to 10% of persons older than 65 years of age have pulmonary hypertension. Moreover, 80% of these persons live in developing countries. Because of prohibitive cost, lack of approved drugs, or limited access to necessary medical and surgical support, these patients are unlikely to receive therapy. An example of necessary support is treatment of chronic thromboembolic pulmonary hypertension (group 4).\u003c\/p\u003e\n\n\u003ch2 id=\"pathology\"\u003eWhat Happens Inside the Blood Vessels\u003c\/h2\u003e\n\n\u003cp\u003eThe histologic features (microscopic appearance of tissues) of pulmonary arterial hypertension are complex and variable because of the multiplicity of underlying diseases. However, there are common pathological features of the disorder.\u003c\/p\u003e\n\n\u003cp\u003eThese features include remodeling of the three layers of the distal pulmonary vasculature (the intima, media, and adventitia). This remodeling involves uncontrolled growth of endothelial and smooth-muscle cells and fibroblasts, as well as infiltration of inflammatory cells. These changes affect primarily precapillary vessels with a caliber of 50 to 500 μm (micrometers).\u003c\/p\u003e\n\n\u003cp\u003eThere is also extension of the smooth-muscle cell layer to typically nonmuscularized distal capillaries. Postcapillary vessels with similar vein remodeling may be involved in specific syndromes. These include pulmonary veno-occlusive diseases and pulmonary capillary hemangiomatosis. These also include scleroderma-associated pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. These further include group 2 cardiac diseases in which vascular remodeling may start in the postcapillary compartment.\u003c\/p\u003e\n\n\u003cp\u003eIn situ thrombosis (blood clot formation inside the vessel) involving small muscular arteries has long been recognized. This is due to platelet activation and loss of endothelial integrity. These changes result in luminal narrowing or complete obliteration of small vessels.\u003c\/p\u003e\n\n\u003cp\u003ePlexiform lesions are common features of pulmonary arterial hypertension. These lesions may arise from anastomoses (connections) involving bronchial arteries or vasa vasorum penetrating the wall structure of pulmonary vessels.\u003c\/p\u003e\n\n\u003cp\u003eEvents leading to severe remodeling have not been clearly identified. However, endothelial dysfunction induced by shear stress, hypoxia, autoimmune phenomena, viral infections, drugs and toxins, or genetic alterations may initiate the process of excess vasoconstriction, inflammation, and uncontrolled cellular growth.\u003c\/p\u003e\n\n\u003cp\u003eThe findings of highly organized lymphoid follicles juxtaposed against pulmonary arterial hypertension lesions have lent substantial credence to a role of inflammation in the pathogenesis of pulmonary arterial hypertension. Infiltration of T and B lymphocytes has also lent substantial credence to this role. Circulating inflammatory markers correlating with disease severity have also lent substantial credence to this role. Additionally, pulmonary arterial hypertension often complicates autoimmune or inflammatory diseases.\u003c\/p\u003e\n\n\u003ch2 id=\"right-ventricle\"\u003eThe Right Ventricle: The Key to Survival\u003c\/h2\u003e\n\n\u003cp\u003eRight ventricular function is the major determinant of clinical outcomes and survival among patients with pulmonary hypertension. In response to an increase in pulmonary vascular resistance by a factor of 5 to 10, the right ventricle undergoes hypertrophy, chamber dilatation, fat deposition, fibrosis, and metabolic shifts. These changes occur as pulmonary hypertension progresses.\u003c\/p\u003e\n\n\u003cp\u003eRight ventricular remodeling may be adaptive or maladaptive:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAdaptive remodeling\u003c\/strong\u003e — concentric hypertrophy (thickening of the heart muscle), preservation of myocardial microcirculation, and minimal fibrosis.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMaladaptive remodeling\u003c\/strong\u003e — eccentric hypertrophy, microvascular rarefaction (loss of small blood vessels) leading to an imbalance between oxygen demand and supply, and myocardial fibrosis.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe mechanisms leading to such changes, or to the transition between these two states, remain poorly understood. They may involve altered angiogenesis (formation of new blood vessels), a shift from glucose oxidation to glycolysis and fatty acid oxidation, and altered mitochondrial bioenergetics.\u003c\/p\u003e\n\n\u003cp\u003ePressure-volume loop technology with a high-fidelity conductance catheter is the standard for assessing right ventricular intrinsic myocardial function and right ventricular-pulmonary vascular coupling. However, this technique is invasive and requires special expertise.\u003c\/p\u003e\n\n\u003cp\u003eSurrogate noninvasive techniques (echocardiography or cardiac magnetic resonance imaging [MRI]) remain to be validated against this standard. Although they do predict outcomes, they are not yet replacements for the invasive gold standard.\u003c\/p\u003e\n\n\u003cp\u003eBetter right ventricular ejection fractions in women than in men free of cardiovascular disease have been attributed to sex hormone differences. These better ejection fractions have also been attributed to sex-related responses to certain drugs (e.g., phosphodiesterase inhibitors and endothelin receptor antagonists). However, further research is warranted.\u003c\/p\u003e\n\n\u003cp\u003eIn vitro study of cardiomyocytes (heart muscle cells) has provided great insight into intrinsic myocardial contractility. These studies revealed a hypercontractile phenotype in patients with idiopathic or congenital heart disease-associated pulmonary arterial hypertension. This is in sharp contrast to a hypocontractile phenotype in patients with scleroderma-associated pulmonary arterial hypertension.\u003c\/p\u003e\n\n\u003cp\u003eThese findings, correlating with in vivo measurements of right ventricular contractility, may explain the worse clinical outcomes and shorter survival in the scleroderma-associated group. The molecular underpinnings of these phenotypes remain poorly studied.\u003c\/p\u003e\n\n\u003ch2 id=\"genetics\"\u003eGenetic Features of PAH\u003c\/h2\u003e\n\n\u003cp\u003eA major breakthrough occurred in 2000, when two independent groups described heterozygous mutations in BMPR2, a member of the transforming growth factor β (TGF-β) superfamily. This breakthrough has substantially advanced our understanding of the role certain genes play in the pathogenesis of pulmonary arterial hypertension. Advances in genetic technology such as whole-genome and whole-exome sequencing have also substantially advanced this understanding.\u003c\/p\u003e\n\n\u003cp\u003eBMPR2 mutations are identified in approximately 80% of patients with familial pulmonary arterial hypertension. There is variable penetrance between male and female carriers. BMPR2 mutations are also found in up to 20% of patients with sporadic disease.\u003c\/p\u003e\n\n\u003cp\u003eIdentification of mutations in ACVRL1 (encoding activin A receptor type II-like 1, also known as activin receptor-like kinase 1) and ENG (encoding endoglin) in families with hereditary hemorrhagic telangiectasia followed rapidly. Hereditary hemorrhagic telangiectasia is a syndrome occasionally complicated by pulmonary arterial hypertension. Both ACVRL1 and endoglin participate in BMPR-II signaling through dimerization.\u003c\/p\u003e\n\n\u003cp\u003eFurther analysis of large cohorts of patients with pulmonary arterial hypertension has identified additional mutations in genes coding for the transcription factors SMAD1, SMAD4, and SMAD9. These are part of the complex BMPR-II downstream signaling. Other genes have been identified in families that are negative for BMPR2 mutations. These include:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eThe gene encoding caveolin-1 (CAV1), which serves to colocalize BMP receptors\u003c\/li\u003e\n  \u003cli\u003eThe gene encoding potassium-channel subfamily K, member 3 (KCNK3), which is implicated in membrane potential maintenance and pulmonary vascular tone\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eMutations in TBX4 (encoding T-box transcription factor 4), a gene associated with small patella syndrome, were detected in a number of children with intellectual disabilities and dystrophic features. These mutations were also detected in some of their parents. These mutations were also detected in an additional small cohort of adults with pulmonary arterial hypertension.\u003c\/p\u003e\n\n\u003cp\u003eBMPR2 mutations predominate in large cohorts. Other new mutations involve:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eATP13A3 (encoding ATPase 13A3)\u003c\/li\u003e\n  \u003cli\u003eSOX17, which encodes SRY-box 17 and is a major risk factor for congenital heart disease-associated pulmonary arterial hypertension\u003c\/li\u003e\n  \u003cli\u003eAQP1 (encoding aquaporin 1)\u003c\/li\u003e\n  \u003cli\u003eGDF2 (encoding growth differentiation factor 2, also known as BMP9)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eBiallelic mutations in EIF2AK4, which encodes the eukaryotic translation initiation factor 2 alpha kinase 4, have been reported in heritable pulmonary capillary hemangiomatosis.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical\"\u003eClinical Presentation and Diagnosis\u003c\/h2\u003e\n\n\u003cp\u003ePatients with pulmonary arterial hypertension typically present with symptoms and signs that reflect the underlying elevation in pulmonary pressures and the strain on the right heart. Common symptoms include exertional dyspnea (shortness of breath with activity), syncope (fainting), elevated jugular-vein pressure, and pedal edema (swelling in the feet and ankles).\u003c\/p\u003e\n\n\u003cp\u003eSigns of connective tissue disease, HIV infection, or liver disease may also be present. Echocardiographic signs are limited to right heart chambers. Other features may include a history of substance abuse (e.g., methamphetamines), exposure to drugs or toxins (e.g., fenfluramine, dexfenfluramine, dasatinib), or family history.\u003c\/p\u003e\n\n\u003cp\u003eThe diagnosis requires a thorough clinical investigation to rule out other, more common forms of pulmonary hypertension. For those other forms, treatment of the underlying disease should be the primary goal.\u003c\/p\u003e\n\n\u003cp\u003eRight heart catheterization is the gold standard for diagnosis. It directly measures the mean pulmonary arterial pressure and calculates the pulmonary vascular resistance. The hemodynamic definition of precapillary pulmonary hypertension is mPAP \u0026gt;20 mm Hg, PAWP ≤15 mm Hg, and PVR ≥3 WU.\u003c\/p\u003e\n\n\u003ch2 id=\"treatment\"\u003eTreatment Approaches\u003c\/h2\u003e\n\n\u003cp\u003eIn the first two decades of this century, a flurry of novel oral, injectable, and inhaled drugs emerged for the treatment of pulmonary arterial hypertension. The development of these drugs followed and was based on various well-conducted, placebo-controlled studies.\u003c\/p\u003e\n\n\u003cp\u003eTargeted therapy is available for pulmonary arterial hypertension. The specific drugs mentioned in this review include phosphodiesterase inhibitors and endothelin receptor antagonists. Sex-related differences in response to these medications have been proposed as a possible explanation for better right ventricular function in women than in men, but further research is warranted.\u003c\/p\u003e\n\n\u003cp\u003eFor patients with other forms of pulmonary hypertension, treatment of the underlying disease should be the primary goal. For example, patients with group 2 pulmonary hypertension due to left-sided heart disease should receive treatment for their heart condition. Patients with group 3 pulmonary hypertension due to lung disease should receive treatment for their lung disease.\u003c\/p\u003e\n\n\u003cp\u003eFor chronic thromboembolic pulmonary hypertension (group 4), medical and surgical support is necessary. This may include pulmonary endarterectomy (surgical removal of clots from the pulmonary arteries).\u003c\/p\u003e\n\n\u003cp\u003eUnfortunately, 80% of persons with pulmonary hypertension live in developing countries. Because of prohibitive cost, lack of approved drugs, or limited access to necessary medical and surgical support, these patients are unlikely to receive therapy.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eWhat This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003ePulmonary arterial hypertension is a serious condition that requires specialized care. Targeted treatments developed over the past two decades have reduced hospitalizations in clinical trials, though the most recent large trials of combined treatment have not shown a clear effect on survival.\u003c\/p\u003e\n\n\u003cp\u003eRight ventricular function is the major determinant of clinical outcomes and survival. This means that protecting the right heart is critical. Patients should work closely with their healthcare team to monitor right heart function through echocardiography or cardiac MRI.\u003c\/p\u003e\n\n\u003cp\u003eGenetic testing may be appropriate for some patients, especially those with a family history of PAH or those with hereditary hemorrhagic telangiectasia. Identifying a genetic mutation can help guide screening for family members and inform treatment decisions.\u003c\/p\u003e\n\n\u003cp\u003eInflammation appears to play a role in PAH. This finding may lead to new treatment approaches targeting the immune system in the future.\u003c\/p\u003e\n\n\u003cp\u003eThe global burden of pulmonary hypertension is enormous. An estimated 1% of the world population and up to 10% of persons older than 65 years have pulmonary hypertension. However, most of these patients live in developing countries where access to care is limited.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations and Unanswered Questions\u003c\/h2\u003e\n\n\u003cp\u003eDespite immense progress, many questions remain unanswered. The events leading to severe vascular remodeling have not been clearly identified. The mechanisms leading to adaptive versus maladaptive right ventricular remodeling, or to the transition between these two states, remain poorly understood.\u003c\/p\u003e\n\n\u003cp\u003eSurrogate noninvasive techniques (echocardiography or cardiac MRI) remain to be validated against the invasive gold standard for assessing right ventricular function. Although they do predict outcomes, they are not yet replacements for pressure-volume loop technology.\u003c\/p\u003e\n\n\u003cp\u003eThe molecular underpinnings of hypercontractile versus hypocontractile phenotypes in different PAH subtypes remain poorly studied.\u003c\/p\u003e\n\n\u003cp\u003eThe prevalence of pulmonary hypertension due to chronic hypoxia among persons living at high altitude is unclear.\u003c\/p\u003e\n\n\u003cp\u003eFurther research is warranted to understand sex-related differences in right ventricular function and responses to certain drugs.\u003c\/p\u003e\n\n\u003cp\u003eMost importantly, 80% of persons with pulmonary hypertension live in developing countries. These persons are unlikely to receive therapy because of prohibitive cost, lack of approved drugs, or limited access to necessary medical and surgical support.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations for Patients\u003c\/h2\u003e\n\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eSeek specialized care.\u003c\/strong\u003e Pulmonary arterial hypertension is a rare condition that requires evaluation by specialists in pulmonary hypertension centers.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eGet an accurate diagnosis.\u003c\/strong\u003e Right heart catheterization is the gold standard for diagnosis. It measures pressures directly and helps distinguish PAH from other forms of pulmonary hypertension.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDiscuss genetic testing.\u003c\/strong\u003e If you have a family history of PAH or hereditary hemorrhagic telangiectasia, genetic testing may be appropriate. Identifying a mutation can help guide screening for family members.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMonitor right heart function.\u003c\/strong\u003e Regular echocardiography or cardiac MRI can help track right ventricular function, which is the major determinant of survival.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAdhere to targeted therapy.\u003c\/strong\u003e Medications such as phosphodiesterase inhibitors and endothelin receptor antagonists have reduced hospitalizations in clinical trials, though the most recent large trials of combined treatment have not shown a clear effect on survival. Work closely with your healthcare team to find the right treatment plan.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eBe aware of sex-related differences.\u003c\/strong\u003e Women may have better right ventricular function than men, and responses to certain drugs may differ by sex. Discuss these factors with your healthcare provider.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAdvocate for access to care.\u003c\/strong\u003e If you live in a developing country or have limited access to care, work with patient advocacy groups to improve access to approved drugs and medical support.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is pulmonary arterial hypertension (PAH)?\u003c\/h3\u003e\n\u003cp\u003ePAH is a rare condition where the blood vessels in the lungs become narrowed and stiff. This forces the right side of the heart to work much harder than normal. It is one of five groups of pulmonary hypertension. Without treatment, PAH can lead to right heart failure and death. Targeted treatments developed over the past two decades have reduced hospitalizations in clinical trials, though the most recent large trials of combined treatment have not shown a clear effect on survival.\u003c\/p\u003e\n\u003ch3\u003eHow is PAH diagnosed?\u003c\/h3\u003e\n\u003cp\u003eDiagnosis requires a thorough clinical investigation to rule out other, more common forms of pulmonary hypertension. Right heart catheterization is the gold standard; it measures pressures directly. PAH is defined by a mean pulmonary arterial pressure above 20 mm Hg at rest, a pulmonary artery wedge pressure of 15 mm Hg or less, and pulmonary vascular resistance of at least 3 Wood units.\u003c\/p\u003e\n\u003ch3\u003eWhat are the symptoms of PAH?\u003c\/h3\u003e\n\u003cp\u003eCommon symptoms include exertional dyspnea (shortness of breath with activity), syncope (fainting), elevated jugular-vein pressure, and pedal edema (swelling in the feet and ankles). Patients may also have signs of connective tissue disease, HIV infection, or liver disease. Echocardiographic signs are limited to right heart chambers. Other features may include a history of substance abuse, exposure to drugs or toxins, or family history.\u003c\/p\u003e\n\u003ch3\u003eIs PAH inherited?\u003c\/h3\u003e\n\u003cp\u003ePAH can be heritable. Mutations in the BMPR2 gene are identified in approximately 80% of patients with familial pulmonary arterial hypertension and in up to 20% of patients with sporadic disease. Other genes have also been linked to PAH. Genetic testing may be appropriate for some patients, especially those with a family history of PAH or hereditary hemorrhagic telangiectasia, to help guide screening for family members.\u003c\/p\u003e\n\u003ch3\u003eWhat treatments are available for PAH?\u003c\/h3\u003e\n\u003cp\u003eTargeted therapies are available for PAH. In the first two decades of this century, novel oral, injectable, and inhaled drugs emerged, including phosphodiesterase inhibitors and endothelin receptor antagonists. These medications have reduced hospitalizations in clinical trials, though the most recent large trials of combined treatment have not shown a clear effect on survival. For other forms of pulmonary hypertension, treatment of the underlying disease should be the primary goal. Patients should work closely with their healthcare team to find the right treatment plan.\u003c\/p\u003e\n\u003ch3\u003eWhy is right heart function important in PAH?\u003c\/h3\u003e\n\u003cp\u003eRight ventricular function is the major determinant of clinical outcomes and survival among patients with pulmonary hypertension. In response to increased pulmonary vascular resistance, the right ventricle undergoes changes such as hypertrophy, chamber dilatation, fat deposition, fibrosis, and metabolic shifts. Protecting the right heart is critical. Regular echocardiography or cardiac MRI can help track right ventricular function.\u003c\/p\u003e\n\u003ch3\u003eWhat is the prognosis for PAH?\u003c\/h3\u003e\n\u003cp\u003eWithout treatment, PAH leads to right heart failure and death. However, targeted treatments developed over the past two decades have reduced hospitalizations in clinical trials, though the most recent large trials of combined treatment have not shown a clear effect on survival. Right ventricular function is the major determinant of survival. Patients should seek specialized care at pulmonary hypertension centers, adhere to therapy, and monitor right heart function regularly with their healthcare team.\u003c\/p\u003e\n\u003ch3\u003eWhen should a patient with newly diagnosed pulmonary arterial hypertension seek a second opinion?\u003c\/h3\u003e\n\u003cp\u003eBecause pulmonary arterial hypertension is rare and requires specialized care, a second opinion is reasonable at diagnosis, since the diagnosis requires thorough clinical investigation to rule out other, more common forms of pulmonary hypertension, for which treatment of the underlying disease is the primary goal. Right heart catheterization is the gold standard and measures pressures directly, distinguishing PAH from other groups. A second review can confirm the group and hemodynamic profile, and clarify whether targeted therapy such as phosphodiesterase inhibitors or endothelin receptor antagonists is appropriate. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal Article Title:\u003c\/strong\u003e Pulmonary Arterial Hypertension NEJM 2021\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e \u003ca href=\"https:\/\/doi.org\/10.1056\/NEJMra2000348\" target=\"_blank\" rel=\"noopener\"\u003e10.1056\/NEJMra2000348\u003c\/a\u003e\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor:\u003c\/strong\u003e Paul M. Hassoun, M.D.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor Affiliation:\u003c\/strong\u003e Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eEditor:\u003c\/strong\u003e Darren B. Taichman, M.D., Ph.D.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e The New England Journal of Medicine, 2021;385:2361-76\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e 10.1056\/NEJMra2000348\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCopyright:\u003c\/strong\u003e © 2021 Massachusetts Medical Society\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47919019655324,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"url":"https:\/\/diagnosticdetectives.com\/da\/products\/pulmonary-arterial-hypertension-a-comprehensive-guide-for-patients","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}