Diagnosis of Pulmonary Arterial Hypertension Paul R. Forfia, MDa,*, Terence K. Trow, MDb,c KEYWORDS Diagnosis Pulmonary Arterial Hypertension Echocardiography Doppler Catheterization
KEY POINTS Diagnosing pulmonary arterial hypertension requires a high index of clinical suspicion and the ability to identify clinical clues of pulmonary vascular disease. The astute clinician should suspect the presence of pulmonary arterial hypertension before performing a right heart catheterization. The echo-Doppler examination is used in part to screen for the presence of increased pulmonary artery pressure. However, this examination provides a great deal more physiologic information about pulmonary hypertension than just pulmonary pressure estimation. The presence of pulmonary vascular disease, and thus high right ventricular afterload, leads to several findings that are unique to these conditions, including right ventricular dilatation, systolic dysfunction, septal flattening and Doppler notching. Patients with pulmonary hypertension not caused by pulmonary vascular disease do not possess these echo-Doppler findings. Right heart catheterization is necessary to establish the hemodynamic criteria of pulmonary arterial hypertension. However, right heart catheterization is subject to pitfalls and thus should be scrutinized carefully to ensure the accuracy of hemodynamic data.
The accurate diagnosis of pulmonary arterial hypertension (PAH) can be a challenging and complex process that requires a high index of clinical suspicion from even the most astute clinician. Because pulmonary vascular disease (PVD) is not the exclusive domain of any given medical discipline, general internists and a broad range of medical specialists alike must be aware of the potential presentations
of this disorder1 as well as the limitations and vagaries of noninvasive tests used to define patients in whom invasive testing is warranted. Right, and sometimes left, heart catheterization is required to establish the diagnosis and to characterize the PAH phenotype before proper treatment can be initiated. This article reviews the evidence supporting the detection and diagnosis of PAH in patients at risk for this disorder.
Disclosures: T.K. Trow has served on speaker’s bureaus for Actelion, Gilead, Lung Rx, and United Therapeutic pharmaceutical (not in the past 12 months). He has also served on advisory boards for Bayer, Actelion, United Therapeutics, Gilead (not in past 12 months). He received funding support as the principal investigator at Yale on the COMPASS II study from Actelion and received funding support as principal investigator on the RESPIRE registry from Actelion. P.R. Forfia has served on speaker’s bureaus for Actelion, Gilead, and United Therapeutic pharmaceutical (not in past 24 months). He has also served as a consultant or member of advisory boards for Bayer, Actelion, United Therapeutics, and Gilead. a Division of Cardiovascular Medicine, Pulmonary Hypertension and Right Heart Failure Program, Temple University Hospital, 3401 North Broad Street, 9th Floor, Parkinson Pavillion, Philadelphia, PA 19140, USA; b Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar Street, PO Box 208057, LLCI 105D, New Haven, CT 06520, USA; c Pulmonary Vascular Disease Program, Yale University School of Medicine, 333 Cedar Street, PO Box 208057, LLCI 105D, New Haven, CT 06520, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med 34 (2013) 665–681 http://dx.doi.org/10.1016/j.ccm.2013.09.001 0272-5231/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
INTRODUCTION
666
Forfia & Trow PATIENT HISTORY The symptoms associated with PAH are nonspecific and are often confounded by the presence of comorbid conditions that might explain them. The National Institutes of Health (NIH) registry found that there was a median of 2 years before the correct diagnosis of PAH was established.2 Dyspnea was the most common initial complaint (60%), followed by syncope, near-syncope or lightheadedness (34%), fatigue (21%), chest pain (8%), and leg edema (7%).2 In the authors’ experience, a classic presentation of PAH occurs when a patient presents with 2 or more complaints within the triad of dyspnea, exertional angina, and exertional near-syncope or syncope. Idiopathic PAH (IPAH) presentations occur more often in young women, often with normal examinations early in their course,3 making reassurance the most common initial intervention. A complaint of exertional angina also may not be sufficiently appreciated by the interviewing physician in this context. Patients often discount their symptoms, often increasing the time before medical attention is sought.3 For this reason, a high index of clinical suspicion should be maintained when an explanation for such symptoms is not readily evident. In addition, conditions with an increased incidence of associated PAH, such as connective tissue disease,4–8 cirrhosis of the liver,9–12 human immunodeficiency virus (HIV) infection, or current or prior history of systemic-to-pulmonary shunt conditions warrant increased concern on the part of the frontline practitioner.
PHYSICAL EXAMINATION Because the number of conditions associated with the development of PAH is extensive, a variety of examination clues may be present and should be looked for. These clues are often subtle and may be overlooked.13 Cardiac auscultation may reveal an accentuated pulmonic component to the second heart sound and delayed closure of the pulmonic valve (split P2) in up to 90% of patients with IPAH.3 This is characteristically fixed without variation during inspiration and expiration in cases of atrial septal defect–associated PAH.14–16 Other signs may include a palpable left parasternal heave, a right ventricular S3 or S4 gallop, prominence of the jugular a wave or v wave, hepatojugular reflux, and lower extremity edema.3 A variety of murmurs may also be encountered on cardiac auscultation, including the high-pitched holosystolic murmur of tricuspid regurgitation (TR) heard best at the left sternal border or the early diastolic high-
pitched murmur of pulmonic regurgitation (PR).15,16 The high pitch of the TR or PR murmur is not typical, and relates to the high velocity of regurgitant flow imparted by high pulmonary artery pressure. Aside from cardiac auscultation, cyanosis is seen in 20% of IPAH cases3 and suggests rightto-left shunting and severe reduction of cardiac output. The sequelae of liver disease, such as testicular atrophy, palmar erythema, and spider telangiectasias, should also be sought. Oral mucosal telangiectasias may suggest a diagnosis of hereditary hemorrhagic telangiectasia (HHT) syndrome, now known to be associated with a mutation in the activin receptor–like kinase-1 (ALK-1) gene in a minority of cases.17 Calcinosis, sclerodactyly, telangiectasias, Raynaud phenomenon, and digital ulcerations may all be seen in scleroderma-associated PAH.14 Because many women with telangiectasias are self-conscious about the skin telangiectasias that appear on their faces, the examiner may need to ask for the removal of facial make-up to appreciate this finding. Digital clubbing is rare in IPAH3 and when present should raise the possibility of congenital heart disease or pulmonary veno-occlusive disease (PVOD).18 A sternotomy scar should alert the clinician to prior chest surgery in a patient with congenital heart disease.
ELECTROCARDIOGRAPHY Although electrocardiography (ECG) lacks sufficient sensitivity and specificity to serve as an effective screening tool19,20 it can contribute important diagnostic and prognostic information and should be performed. Right ventricular hypertrophy (RVH) and right-axis deviation (RAD) can be detected 87% and 79% of the time, respectively, in PAH.3 Features of RVH suggesting PAH include a tall R wave and small S wave (R/S ratio of >1) in lead V1, a large S wave and small R wave (R/S ratio25 mm Hg, PAWP>15 mm Hg, and PVR
KEY POINTS Diagnosing pulmonary arterial hypertension requires a high index of clinical suspicion and the ability to identify clinical clues of pulmonary vascular disease. The astute clinician should suspect the presence of pulmonary arterial hypertension before performing a right heart catheterization. The echo-Doppler examination is used in part to screen for the presence of increased pulmonary artery pressure. However, this examination provides a great deal more physiologic information about pulmonary hypertension than just pulmonary pressure estimation. The presence of pulmonary vascular disease, and thus high right ventricular afterload, leads to several findings that are unique to these conditions, including right ventricular dilatation, systolic dysfunction, septal flattening and Doppler notching. Patients with pulmonary hypertension not caused by pulmonary vascular disease do not possess these echo-Doppler findings. Right heart catheterization is necessary to establish the hemodynamic criteria of pulmonary arterial hypertension. However, right heart catheterization is subject to pitfalls and thus should be scrutinized carefully to ensure the accuracy of hemodynamic data.
The accurate diagnosis of pulmonary arterial hypertension (PAH) can be a challenging and complex process that requires a high index of clinical suspicion from even the most astute clinician. Because pulmonary vascular disease (PVD) is not the exclusive domain of any given medical discipline, general internists and a broad range of medical specialists alike must be aware of the potential presentations
of this disorder1 as well as the limitations and vagaries of noninvasive tests used to define patients in whom invasive testing is warranted. Right, and sometimes left, heart catheterization is required to establish the diagnosis and to characterize the PAH phenotype before proper treatment can be initiated. This article reviews the evidence supporting the detection and diagnosis of PAH in patients at risk for this disorder.
Disclosures: T.K. Trow has served on speaker’s bureaus for Actelion, Gilead, Lung Rx, and United Therapeutic pharmaceutical (not in the past 12 months). He has also served on advisory boards for Bayer, Actelion, United Therapeutics, Gilead (not in past 12 months). He received funding support as the principal investigator at Yale on the COMPASS II study from Actelion and received funding support as principal investigator on the RESPIRE registry from Actelion. P.R. Forfia has served on speaker’s bureaus for Actelion, Gilead, and United Therapeutic pharmaceutical (not in past 24 months). He has also served as a consultant or member of advisory boards for Bayer, Actelion, United Therapeutics, and Gilead. a Division of Cardiovascular Medicine, Pulmonary Hypertension and Right Heart Failure Program, Temple University Hospital, 3401 North Broad Street, 9th Floor, Parkinson Pavillion, Philadelphia, PA 19140, USA; b Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar Street, PO Box 208057, LLCI 105D, New Haven, CT 06520, USA; c Pulmonary Vascular Disease Program, Yale University School of Medicine, 333 Cedar Street, PO Box 208057, LLCI 105D, New Haven, CT 06520, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med 34 (2013) 665–681 http://dx.doi.org/10.1016/j.ccm.2013.09.001 0272-5231/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
INTRODUCTION
666
Forfia & Trow PATIENT HISTORY The symptoms associated with PAH are nonspecific and are often confounded by the presence of comorbid conditions that might explain them. The National Institutes of Health (NIH) registry found that there was a median of 2 years before the correct diagnosis of PAH was established.2 Dyspnea was the most common initial complaint (60%), followed by syncope, near-syncope or lightheadedness (34%), fatigue (21%), chest pain (8%), and leg edema (7%).2 In the authors’ experience, a classic presentation of PAH occurs when a patient presents with 2 or more complaints within the triad of dyspnea, exertional angina, and exertional near-syncope or syncope. Idiopathic PAH (IPAH) presentations occur more often in young women, often with normal examinations early in their course,3 making reassurance the most common initial intervention. A complaint of exertional angina also may not be sufficiently appreciated by the interviewing physician in this context. Patients often discount their symptoms, often increasing the time before medical attention is sought.3 For this reason, a high index of clinical suspicion should be maintained when an explanation for such symptoms is not readily evident. In addition, conditions with an increased incidence of associated PAH, such as connective tissue disease,4–8 cirrhosis of the liver,9–12 human immunodeficiency virus (HIV) infection, or current or prior history of systemic-to-pulmonary shunt conditions warrant increased concern on the part of the frontline practitioner.
PHYSICAL EXAMINATION Because the number of conditions associated with the development of PAH is extensive, a variety of examination clues may be present and should be looked for. These clues are often subtle and may be overlooked.13 Cardiac auscultation may reveal an accentuated pulmonic component to the second heart sound and delayed closure of the pulmonic valve (split P2) in up to 90% of patients with IPAH.3 This is characteristically fixed without variation during inspiration and expiration in cases of atrial septal defect–associated PAH.14–16 Other signs may include a palpable left parasternal heave, a right ventricular S3 or S4 gallop, prominence of the jugular a wave or v wave, hepatojugular reflux, and lower extremity edema.3 A variety of murmurs may also be encountered on cardiac auscultation, including the high-pitched holosystolic murmur of tricuspid regurgitation (TR) heard best at the left sternal border or the early diastolic high-
pitched murmur of pulmonic regurgitation (PR).15,16 The high pitch of the TR or PR murmur is not typical, and relates to the high velocity of regurgitant flow imparted by high pulmonary artery pressure. Aside from cardiac auscultation, cyanosis is seen in 20% of IPAH cases3 and suggests rightto-left shunting and severe reduction of cardiac output. The sequelae of liver disease, such as testicular atrophy, palmar erythema, and spider telangiectasias, should also be sought. Oral mucosal telangiectasias may suggest a diagnosis of hereditary hemorrhagic telangiectasia (HHT) syndrome, now known to be associated with a mutation in the activin receptor–like kinase-1 (ALK-1) gene in a minority of cases.17 Calcinosis, sclerodactyly, telangiectasias, Raynaud phenomenon, and digital ulcerations may all be seen in scleroderma-associated PAH.14 Because many women with telangiectasias are self-conscious about the skin telangiectasias that appear on their faces, the examiner may need to ask for the removal of facial make-up to appreciate this finding. Digital clubbing is rare in IPAH3 and when present should raise the possibility of congenital heart disease or pulmonary veno-occlusive disease (PVOD).18 A sternotomy scar should alert the clinician to prior chest surgery in a patient with congenital heart disease.
ELECTROCARDIOGRAPHY Although electrocardiography (ECG) lacks sufficient sensitivity and specificity to serve as an effective screening tool19,20 it can contribute important diagnostic and prognostic information and should be performed. Right ventricular hypertrophy (RVH) and right-axis deviation (RAD) can be detected 87% and 79% of the time, respectively, in PAH.3 Features of RVH suggesting PAH include a tall R wave and small S wave (R/S ratio of >1) in lead V1, a large S wave and small R wave (R/S ratio25 mm Hg, PAWP>15 mm Hg, and PVR
