Targeted therapies in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of small pulmonary arteries that leads to elevated pulmonary arterial pressure and right heart failure. During the last decades, an improved understanding of the pathophysiology of the disease has resulted in the development of effective therapies targeting endothelial dysfunction (epoprostenol and derivatives, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors). These drugs allow clinical, functional and hemodynamic improvement. Even though, no cure exists for PAH and prognosis remains poor. Recently, several additional pathways have been suggested to be involved in the pathogenesis of PAH, and may represent innovative therapies. In this summary, we review conventional therapy, pharmacological agents currently available for the treatment of PAH and the benefit/risk ratio of potential future therapies.     

Why there is a need to discuss pulmonary hypertension other than pulmonary arterial hypertension?

Pulmonary hypertension(PH) is a condition characterized by the elevation of the mean pulmonary artery pressure above 25 mm Hg and the pulmonary vascular resistance above 3 wood units. Pulmonary arterial hypertension(PAH) is an uncommon conditionwith severe morbidity and mortality, needing early recognition and appropriate and specific treatment. PH is frequently associated with hypoxemia, mainly chronic obstructive pulmonary disease and DPLD and/or left heart diseases(LHD), mainly heart failure with reduced or preserved ejection fraction. Although in the majority of patients with PH the cause is not PAH, a significant number of published studies are still in regard to group Ⅰ PH, leading to a logical assumption that PH due to other causes is not such an important issue. So, is there a reason to discuss PH other than PAH? Chronic lung diseases, mainly chronic obstructive lung disease and DPLD, are associated with a high incidence of PH which is linked to exercise limitations and a worse prognosis. Although pathophysiological studies suggest that specific PAH therapy may benefit such patients, the results presented from small studies in regard to the safety and effectiveness of the specific PAH therapy are discouraging. PH is a common complication of left heart disease and is related to disease severity, especially in patients with reduced ejection fraction. There are two types of PH related to LHD based on diastolic pressure difference(DPD, defined as diastolic pulmonary artery pressure- mean PAWP): Isolated post-capillary PH, defined as PAWP 15 mm Hg and DPD 7 mm Hg, and combined post-capillary PH and pre-capillary PH, defined as PAWP 15 mm Hg and DPD ≥ 7 mm Hg. The potential use of PAH therapies in patients with PH related to left heart disease is based on a logical pathobiological rationale. In patients with heart failure, endothelial dysfunction has been proposed as a cause of PH and hence as a target for treatment, supported by the presence of increased endothelin-1 activity and impaired nitric oxide-dependent vasodilation. Unfortunately, so far, there is no evidence supporting the use of specific PAH therapies in patients with PH related to left heart disease. In conclusion, the presence of PH in patients with conditions other than PAH contributes to the severity of the disease, affecting the outcome and quality of life. The disappointing results regarding the effectiveness of specific PAH therapies in patients withchronic lung diseases and LHD underline the need for seeking new underlying mechanisms and thus novel therapies targeting PH due to left heart disease and/or lung diseases.     

Pulmonary Arterial Hypertension: A Palliative Medicine Review of the Disease,Its Therapies,and Drug Interactions

Pulmonary arterial hypertension (PAH) is often a progressive and ultimately fatal disease. It is characterized by an elevated mean pulmonary arterial pressure because of disease of the small pulmonary arterioles. PAH leads to a constellation of symptoms, including dyspnea, fatigue, syncope, chest discomfort, and peripheral edema. Disease-targeted therapies for PAH produce symptomatic and functional improvement, but long-term survival remains uncommon without lung transplantation. Palliative care is appropriate to support patients with advanced PAH who typically have a high symptom burden. However, palliative care has historically focused on supporting patients with malignant disease, rather than progressive chronic disease such as PAH. Our aim is to provide palliative care clinicians with a background in the classification, pathophysiology, and modern treatment of PAH. This review describes disease-targeted therapies and their effects on symptoms, physical functioning, and health-related quality of life. We also review the unique physiology of PAH and its implication for palliative interventions. Pharmacological interactions with, and precautions related to commonly used palliative care medications, are discussed.     

肺动脉高压动物模型与分子机制的研究进展

肺动脉高压（PAH）是一种以肺末梢小动脉增生重构促进肺动脉压力和阻力进行性增加为特征的严重疾病。其发病机制十分复杂,多种致病因子参与其发生发展过程。本文探讨肺动脉的离子稳态、骨形成蛋白、血管活性物质等细胞信号因子在PAH中的致病机制,为PAH分子水平干预和早期临床康复介入提供新的治疗靶点。因此,本文就目前PAH的动物造模的研究方法以及与PAH血管重构关键信号通路进行综述。     

Recent progress in the treatment of pulmonary arterial hypertension: expectation for rho-kinase inhibitors

Pulmonary arterial hypertension (PAH) is a disease with poor prognosis characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary artery hyperconstriction and remodeling. However, the precise mechanism of PAH still remains to be elucidated. Although anticoagulant agents, vasodilators (e.g., prostaglandins, sildenafil, and bosentan), and lung transplantation are currently used for the treatment of PAH, more effective treatment needs to be developed. Rho-kinase causes vascular smooth muscle hyperconstriction and vascular remodeling through inhibition of myosin phosphatase and activation of its downstream effectors. In a series of experimental and clinical studies, we have demonstrated that Rho-kinase-mediated pathway plays an important role in various cellular functions, not only in vascular smooth muscle hyperconstriction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expression, all of which may be involved in the pathogenesis of arteriosclerosis. We also have recently demonstrated that Rho-kinase is activated in animal models of PAH with different etiologies (monocrotaline and chronic hypoxia) associated with enhanced pulmonary vasoconstricting and proliferating responses, impaired endothelial vasodilator functions, and pulmonary remodeling. Indeed, we were able to demonstrate that intravenous fasudil, a selective Rho-kinase inhibitor, exerts acute pulmonary vasodilator effects in patients with severe PAH who were refractory to conventional therapies. Taken together, our findings indicate that Rho-kinase is a novel and important therapeutic target of PAH in humans and that Rho-kinase inhibitors are a promising new class of drugs for the fatal disorder.     

High levels of zinc-protoporphyrin identify iron metabolic abnormalities in pulmonary arterial hypertension

Iron homeostasis influences the development of pulmonary arterial hypertension (PAH) associated with hypoxia or hematologic disorders. To investigate whether severity of idiopathic PAH (IPAH) is impacted by alterations in iron metabolism, we assessed iron metabolic markers, including levels of zinc-protoporphyrin (Zn-pp), transferrin receptor, and red blood cell numbers and morphology in IPAH, associated PAH and sleep apnea-induced pulmonary hypertension patients in comparison to healthy controls and asthmatics. Despite similarly normal measures of iron metabolism, Zn-pp levels in IPAH and sleep apnea patients were elevated approximately twofold, indicating deficient iron incorporation to form heme and levels were closely related to measures of disease severity. Consistent with high Zn-pp, PAH patients had increased red cell distribution width (RDW). In an expanded cohort including patients with IPAH and familial disease, the RDW was validated and related to clinical parameters of severity; including pulmonary artery pressures and 6-minute walk distances. These results reveal an increased prevalence of subclinical functional iron deficiency in primary forms of PAH that is quantitatively related to disease severity. This suggests that altered iron homeostasis influences disease progression and demonstrates the importance of closely monitoring iron status in PAH patients.     

Inhibition of MRP4 prevents and reverses pulmonary hypertension in mice

Multidrug resistance-associated protein 4 (MRP4, also known as Abcc4) regulates intracellular levels of cAMP and cGMP in arterial SMCs. Here, we report our studies of the role of MRP4 in the development and progression of pulmonary arterial hypertension (PAH), a severe vascular disease characterized by chronically elevated pulmonary artery pressure and accompanied by remodeling of the small pulmonary arteries as a prelude to right heart failure and premature death. MRP4 expression was increased in pulmonary arteries from patients with idiopathic PAH as well as in WT mice exposed to hypoxic conditions. Consistent with a pathogenic role for MRP4 in PAH, WT mice exposed to hypoxia for 3 weeks showed reversal of hypoxic pulmonary hypertension (PH) following oral administration of the MRP4 inhibitor MK571, and Mrp4-/- mice were protected from hypoxic PH. Inhibition of MRP4 in vitro was accompanied by increased intracellular cAMP and cGMP levels and PKA and PKG activities, implicating cyclic nucleotide-related signaling pathways in the mechanism underlying the protective effects of MRP4 inhibition. Our data suggest that MRP4 could represent a potential target for therapeutic intervention in PAH.     

Pulmonary Arterial Hypertension: Early Recognition and Treatment Can Make a Lifetime Difference for Your Patient

Pulmonary arterial hypertension (PAH) is a rare, life-threatening, progressive disease that is characterized by sustained elevations of pulmonary artery pressure with no apparent cause. Because it is often difficult to diagnose, the true incidence of PAH is unknown. The true number of cases has eluded researchers because accurate diagnosing of PAH is complex. The prevalence of PAH is estimated at 1 to 2 million people worldwide, with 500 to 1000 new cases diagnosed in the United States each year. It is important for nurse practitioners who work in both primary and acute care to be familiar with this devastating disease and to consider this condition as a differential diagnosis when caring for patients with dyspnea.     

High Levels of Zinc‐Protoporphyrin Identify Iron Metabolic Abnormalities in Pulmonary Arterial Hypertension

Iron homeostasis influences the development of pulmonary arterial hypertension (PAH) associated with hypoxia or hematologic disorders. To investigate whether severity of idiopathic PAH (IPAH) is impacted by alterations in iron metabolism, we assessed iron metabolic markers, including levels of zinc‐protoporphyrin (Zn‐pp), transferrin receptor, and red blood cell numbers and morphology in IPAH, associated PAH and sleep apnea‐induced pulmonary hypertension patients in comparison to healthy controls and asthmatics. Despite similarly normal measures of iron metabolism, Zn‐pp levels in IPAH and sleep apnea patients were elevated approximately twofold, indicating deficient iron incorporation to form heme and levels were closely related to measures of disease severity. Consistent with high Zn‐pp, PAH patients had increased red cell distribution width (RDW). In an expanded cohort including patients with IPAH and familial disease, the RDW was validated and related to clinical parameters of severity; including pulmonary artery pressures and 6‐minute walk distances. These results reveal an increased prevalence of subclinical functional iron deficiency in primary forms of PAH that is quantitatively related to disease severity. This suggests that altered iron homeostasis influences disease progression and demonstrates the importance of closely monitoring iron status in PAH patients. Clin Trans Sci 2011; Volume 4: 253–258     

Primary pulmonary hypertension: an overview of epidemiology and pathogenesis

Pulmonary arterial hypertension (PAH) refers to a group of diseases characterized by high pulmonary artery pressure of unknown mechanism. Primary pulmonary hypertension (PPH) is the idiopathic subset of PAH that affects a mostly young population and is more common in females than in males. A familial form of PPH accounts for about 6% of cases, and its autosomal dominant gene was recently identified. Pulmonary arterial hypertension is histologically characterized by endothelial and smooth muscle cell proliferation, medial hypertrophy, and thrombosis in situ. The pathogenesis of PAH remains unclear. Elevated pulmonary vascular resistance seems to result from an imbalance between locally produced vasodilators and vasoconstrictors, in addition to vascular wall remodeling. Nitric oxide, a locally produced selective pulmonary vasodilator, appears to play a central role in the pathobiology of PAH.     

第六届世界肺高血压会议:聚焦肺高血压定义与诊断分类更新

第六届世界肺高血压会议对肺高血压(pulmonary hypertension, PH)的定义和诊断分类进行了修订和更新。PH的血流动力学定义维持不变, 将毛细血管前性PH定义更新为:肺动脉平均压＞20 mm Hg、肺动脉楔压 < 15 mm Hg且肺血管阻力> 3 WU。诊断分类更新包括:增加急性肺血管扩张试验阳性肺动脉高压(pulmonary arterial hypertension, PAH)亚类, 将甲基苯丙胺(冰毒)和达沙替尼致PAH作用由可能升级为肯定, 将肺静脉闭塞病/肺毛细血管瘤病由特殊的1'更新为PAH的一个亚类, 将脾切除术后和甲状腺疾病从PH诊断分类中移除等。本次PH定义和诊断分类更新将为临床实践提供重要指导意义。     

Pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare and debilitating disease characterized by abnormal proliferation and contraction of pulmonary vascular smooth muscle cells. The resulting increase in pressure and pulmonary vascular resistance results in progressive right heart failure, low cardiac output, and ultimately death if left untreated. PAH is defined by a persistent elevation in pulmonary artery pressure with normal left-sided pressures, differentiating it from left-sided heart disease. Symptoms progress from shortness of breath and decreasing exercise tolerance to right heart failure, with peripheral edema and marked functional limitation. Exercise-induced syncope, worsening symptoms at rest, and intractable right heart failure indicate critical disease. PAH may be idiopathic with no identifiable cause or associated with collagen vascular diseases, drugs, HIV, liver disease, and/or congenital heart disease. Familial or genetically mediated PAH accounts for a small percentage of cases. Advances in the understanding of pathobiological pathways that contribute to vascular proliferation and remodeling have resulted in new therapies that improve quality of life and survival. Emerging therapies focus on the nitric oxide, prostacyclin, and endothelin pathways. Nursing interventions are critical to ensure patients' success with these expensive and complex treatments and their optimal adjustment to living with PAH.     

Hypertension artérielle pulmonaire primitive

Pulmonary hypertension is defined by a mean pulmonary artery pressure higher than 25 mmHg at rest, associated with a pulmonary capillary pressure lower than 12 mmHg. Despite the development of echocardiography, right heart catheterism remains the gold standard in the diagnosis of pulmonary hypertension. Because of the persistent confusion between primary and secondary pulmonary hypertension, a new classification was proposed in 1998. Primary pulmonary hypertension is rare with a prevalence of 2 cases/million people/year, whereas secondary pulmonary hypertension is more frequent, associated with COPD or thromboembolic disease. In twenty percent of patients, vasodilatators are responsible for a significant decrease in mean pulmonary artery pressure and in pulmonary vascular resistance. Vasodilatators, and especially epoprostenol, are responsible for a decrease in mortality. Pulmonary transplantation is proposed in the severest cases with a 50% mortality 5 years after the surgical treatment.     

Soluble TWEAK predicts hemodynamic impairment and functional capacity in patients with pulmonary arterial hypertension

Soluble TWEAK is a member of the TNF-alpha family of cytokines that has been shown to predict mortality in patients with heart failure. Pulmonary artery hypertension is a devastating disease, in which right ventricular function has been shown to be the major determinant of prognosis. In this hypothesis-generating study, we sought to evaluate the potential usefulness of sTWEAK in the prediction of disease severity in patients with pulmonary artery hypertension. We therefore conducted a retrospective analysis of sTWEAK serum levels in 95 stable patients with PAH. For all patients data on hemodynamic parameters, biomarkers and functional exercise tests were available. Compared to controls, patients with PAH showed significantly decreased levels of sTWEAK [median 314 pg/ml (interquartile range 217–473 pg/ml) vs. 405 (321–496 pg/ml); PAH vs. controls; P < 0.0001]. Soluble TWEAK levels were inversely correlated with NYHA class, pulmonary artery pressure, pulmonary vascular resistance, NT-proBNP, and troponin T levels and directly correlated with cardiac index, reduced 6-min walk test distances, and peak oxygen consumption. ROC curve analysis of sTWEAK levels in PAH patients revealed a cutoff value of 306 pg/ml for sTWEAK to be predictive of a reduced exercise capacity (6-min walk test <300 m) in patients with PAH with a similar predictive value compared to NT-proBNP. Intraindividual serial evaluation of sTWEAK revealed the potential of sTWEAK as follow-up marker in patients with PAH. In our hypothesis-generating study, sTWEAK was closely correlated to hemodynamic, functional, and serological indices of outcome in patients with PAH. Further prospective studies are needed to determine the role of sTWEAK as potential biomarker in patients with PAH.     

Chronic active Epstein-Bar virus infection complicated by pulmonary artery hypertension

Chronic active Epstein-Bar virus infection (CAEBV) is known to cause various symptoms. Although pulmonary artery hypertension (PAH) has been reported as a cardiovascular complication of CAEBV, the mechanisms of PAH and the effects of treatment have not been fully elucidated.We experienced 4 adult patients with CAEBV complicated by PAH. All of them received treatment for PAH with a vasodilator followed by chemotherapy with or without allogeneic hematopoietic cell transplantation for CAEBV. In all of these patients, the transtricuspid pressure gradient improved under treatment with vasodilator, and further improvement was observed under treatment for CAEBV in 3 patients. Autopsy was performed in 2 patients, which revealed EBER-positive cells and a change in the pulmonary artery at each stage in the pathology. In conclusion, EBV-infected cells can cause vasculitis and finally PAH. However, PAH complicated with CAEBV can be improved by PAH medication and treatment of CAEBV.     

Wall shear stress measured by phase contrast cardiovascular magnetic resonance in children and adolescents with pulmonary arterial hypertension

Background

Pulmonary arterial hypertension (PAH) is a devastating disease with significant morbidity and mortality. At the macroscopic level, disease progression is observed as a complex interplay between mean pulmonary artery pressure, pulmonary vascular resistance, pulmonary vascular stiffness, arterial size, and flow. Wall shear stress (WSS) is known to mediate or be dependent on a number of these factors. Given that WSS is known to promote architectural vessel remodeling, it is imperative that the changes of this factor be quantified in the presence of PAH.

Methods

In this study, we analyzed phase contrast imaging of the right pulmonary artery derived from cardiovascular magnetic resonance to quantify the local, temporal and circumferentially averaged WSS of a PAH population and a pediatric control population. In addition, information about flow and relative area change were derived.

Results

Although the normotensive and PAH shear waveform exhibited a WSS profile which is uniform in magnitude and direction along the vessel circumference at systole, time-averaged WSS (2.2 ± 1.6 vs. 6.6 ± 3.4 dynes/cm², P = 0.018) and systolic WSS (8.2 ± 5.0 v. 20.0 ± 9.1 dynes/cm², P = 0.018) was significantly depressed in the PAH population as compared to the controls. BSA-indexed PA diameter was significantly larger in the PAH population (1.5 ± 0.4 vs. 0.7 ± 0.1 cm/m², P = 0.003).

Conclusions

In the presence of preserved flow rates through a large PAH pulmonary artery, WSS is significantly decreased. This may have implications for proximal pulmonary artery remodeling and cellular function in the progression of PAH.     

Pulmonary Hypertension: Evaluation and Management

Pulmonary hypertension (PH) is a hemodynamic state characterized by elevation in the mean pulmonary arterial pressure and pulmonary vascular resistance leading to right ventricular failure and premature death. PH can be the result of a variety of diseases of different etiologies. Pulmonary arterial hypertension (PAH) should be distinctly differentiated from pulmonary venous hypertension (PVH) as a result of left heart disease. PAH is commonly caused by or associated with an underlying pulmonary, cardiac, or systemic disease (APAH). In the absence of an identifiable etiology or associated underlying disease, PAH is referred to as idiopathic (IPAH). IPAH, formerly known as primary pulmonary hypertension (PPH), is a rare disease most commonly seen in women of childbearing age. Presenting symptoms and signs are nonspecific and include dyspnea on exertion, fatigue, and a loud pulmonary component of the second heart sound. Transthoracic Doppler echocardiography is an excellent noninvasive test to detect the presence of pulmonary hypertension, although every patient should receive a right heart catheterization to confirm the diagnosis. A detailed work up, including laboratory tests and imaging studies, is also indicated to rule out known causes of pulmonary hypertension. Several targeted treatment options have become available in recent years and include parenteral and inhaled prostanoids, oral endothelin receptor antagonists, and oral phosphodiesterase type-5 inhibitors. As a result of their complex care, patients should be referred to centers with expertise in pulmonary hypertension.     

Lessons learned from cancer may help in the treatment of pulmonary hypertension

Hyperplasia of pulmonary artery SMCs (PASMCs) is a pathological hallmark of pulmonary arterial hypertension (PAH). In this issue of the JCI, McMurtry et al. report that adenovirus-mediated overexpression of survivin--a multipotent inhibitor of apoptosis--induces PAH in rats, whereas inhalation of an adenovirus vector encoding a mutant survivin gene with dominant-negative properties reverses established monocrotaline-induced PAH. These findings raise important issues regarding the role of survivin in the pathogenesis of PAH, its value as a prognostic indicator, and its use as a target for new therapeutic strategies.     

Contrast echocardiography of the left ventricle an independent predictor of pulmonary artery pressure?

To test the hypothesis that left heart opacification is dependent on pulmonary artery pressure, we analyzed consecutively 12 patients with normal and 8 patients with abnormal pulmonary artery pressure with a new lung capillary stable echo contrast agent. Patients underwent contrast echocardiographic examination within 6 hours before right and left heart catheterization with 200 mg/ml and 400 mg/ml SHU 508A intravenously. The mean pulmonary artery pressure was 15.4 mmHg in the patients with normal pulmonary artery pressures and 46.4 mmHg in the patients with pulmonary hypertension (p< 0.000). Echocardiograms were video-intensitometrically analyzed for intensity maximum (MAX), half-time of video-intensity decay (T1/2), area under the intensity curve (AUC) in the right and left ventricle and transit time from left to right heart (TT). Patients with normal pulmonary artery pressure showed sufficient left heart opacification, in the left ventricle MAX was 37±15 IU, AUC measured 653±463 IUxs and Tl/2 was 4.4±2.6 s, while patients with elevated pulmonary artery pressure showed no significant left heart opacification. In the left ventricle MAX was 8±10 IU (p=0.006), AUC measured 66±108 (p=0.003) and T1/2 was 2.0±2.0 s (p=0.041). TT was significantly increased in patients with elevated pulmonary artery pressure (11.8±4.6 s versus 6.5±2.8 s in patients with normal pulmonary artery pressure, p=0.005). Thus, elevated pulmonary pressure has a significant impact on left heart opacification, which may be used for diagnostic purposes.     

Comparison of body habitus in patients with pulmonary arterial hypertension enrolled in the Registry to Evaluate Early and Long-term PAH Disease Management with normative values from the National Health and Nutrition Examination Survey

OBJECTIVE: To investigate the correlation between body mass index (BMI) and pulmonary artery systolic pressure in a large population of patients with pulmonary arterial hypertension (PAH).PATIENTS AND METHODS: The BMI of patients with group 1 PAH enrolled in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) was compared with that of age- and sex-matched controls in the National Health and Nutrition Examination Survey (NHANES) to clarify whether obesity is linked with PAH. The diagnosis of PAH was defined in REVEAL by right-sided heart catheterization. Differences in BMI and the percentage of patients considered obese (BMI ≥30) and underweight (BMI <18.5) in various subgroups of patients enrolled in REVEAL from March 30, 2006, through September 11, 2007, were determined.RESULTS: Mean BMI was no different for patients with PAH (n=2141) than for the NHANES normal comparison group; however, the proportion of obese and underweight patients was increased in patients with PAH. Subgroup analysis demonstrated that subgroups with idiopathic PAH and those with PAH associated with drugs and toxins had both higher BMI and percentage of obese patients, whereas 3 other subgroups (those with PAH associated with congenital heart disease, connective tissue disease, and human immunodeficiency virus) had lower mean BMI.CONCLUSION: Mean BMI of the REVEAL patients was the same as that of the NHANES normal comparison group; however, there were higher percentages of obese and underweight patients in REVEAL. This discrepancy can be explained by the balancing effect of more overweight and underweight patients in different PAH subgroups. The reason for the increased frequency of obesity in idiopathic PAH is unknown, and additional study is needed.Trial Registration: clinicaltrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00370214","term_id":"NCT00370214"}}NCT00370214APAH = associated PAH; BMI = body mass index; CHD-APAH = congenital heart disease–APAH; CTD-APAH = connective tissue disease–APAH; FPAH = familial PAH; HIV-APAH = human immunodeficiency virus infection–APAH; IPAH = idiopathic PAH; LVEDP = left ventricular end-diastolic pressure; NHANES = National Health and Nutrition Examination Survey; PAH = pulmonary arterial hypertension; PAP = pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PH = pulmonary hypertension; REVEAL = Registry to Evaluate Early and Long-term PAH Disease Management; RHC = right-sided heart catheterizationData from the National Health and Nutrition Examination Survey (NHANES) have demonstrated that 35% of US adults are classified as obese (body mass index [BMI], calculated as the weight in kilograms divided by the height in meters squared, ≥30).^1,2 In addition, up to 46% of patients with pulmonary arterial hypertension (PAH) have no clear cause for the disease (ie, idiopathic PAH [IPAH]).³ Although obesity is epidemic in the United States,^1,2 comprehensive reviews have listed obesity as an unlikely risk factor for PAH.⁴ However, there are no confirmed reports of a direct correlation of obesity with clinically significant PAH. Although a correlation between BMI and pulmonary artery systolic pressure has been identified in otherwise echocardiographically normal persons (Spearman rank correlation, 0.19; P<.01; N=3790),⁵ a retrospective review of 401 patients in the pulmonary hypertension (PH) database of Mayo Clinic in Florida found no correlation between BMI and diagnosis of PH when these patients were compared with controls (n=578).⁶PAH is characterized by mean pulmonary artery pressure (PAP) of 25 mm Hg or greater and pulmonary capillary wedge pressure (PCWP) of 15 mm Hg or less.^3,7 Group 1 PH comprises 5 categories: IPAH, familial PAH (FPAH; now referred to as heritable PAH), associated PAH (APAH; including PAH associated with connective tissue disease [CTD-APAH], drugs and toxins-PAH), congenital heart disease [CHD-APAH], human immunodeficiency virus infection [HIV-APAH], portal hypertension, schistosomiasis, and chronic hemolytic anemia), and persistent PH of the newborn.⁸The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) represents a unique opportunity to examine the potential relationship between obesity and PAH. REVEAL is a prospective study initiated to characterize the demographics, clinical course, hemodynamic features, and disease management of about 3500 US patients with group 1 PH.^3,9 This large database of patients with PAH permits a robust analysis of BMI and the percentage of overweight and underweight patients with PAH. REVEAL also provides an opportunity to identify potential associated risk factors in patients with IPAH, which, if confirmed, may generate hypothesis-based investigations to help determine causal links. In the current study, we compared patients in the REVEAL database with age- and sex-matched controls from NHANES to determine whether a relationship exists between BMI and the presence of PAH.