2004ACCP+肺动脉高压的筛查、早期检测及诊断

DOI 10.1378/chest.126.1_suppl.14S 2004;126;14S-34SChest Douglas C. McCrory, Terry A. Fortin and James E. Loyd Michael McGoon, David Gutterman, Virginia Steen, Robin Barst, Evidence-Based Clinical Practice Guidelines : ACCP*Pulmonary Arterial Hypertension Screening, Early Detection, and Diagnosis of http://chestjournal.chestpubs.org/content/126/1_suppl/14S.full.html services can be found online on the World Wide Web at: The online version of this article, along with updated information and 14S.DC1.html http://chestjournal.chestpubs.org/content/suppl/2004/07/06/126.1_suppl. Supplemental material related to this article is available at: ISSN:0012-3692 )http://chestjournal.chestpubs.org/site/misc/reprints.xhtml( written permission of the copyright holder. this article or PDF may be reproduced or distributed without the prior Dundee Road, Northbrook, IL 60062. All rights reserved. No part of Copyright2004by the American College of Chest Physicians, 3300 Physicians. It has been published monthly since 1935. is the official journal of the American College of ChestChest © 2004 American College of Chest Physicians by guest on August 24, 2011chestjournal.chestpubs.orgDownloaded from Screening, Early Detection, and Diagnosis of Pulmonary Arterial Hypertension* ACCP Evidence-Based Clinical Practice Guidelines Michael McGoon, MD; David Gutterman, MD, FCCP; Virginia Steen, MD; Robin Barst, MD; Douglas C. McCrory, MD, MHS; Terry A. Fortin, MD; and James E. Loyd, MD, FCCP Pulmonary arterial hypertension (PAH) occurs as an idiopathic process or as a component of a variety of disease processes, including chronic thromboembolic disease, connective tissue diseases, congenital heart disease, and exposure to exogenous factors including appetite suppres- sants or infectious agents such as HIV. This article reviews evidence for screening in susceptible patient groups and the approach to diagnosing PAH when it is suspected, and provides specific recommendations for applying this evidence to clinical practice. (CHEST 2004; 126:14S–34S) Key words: catheterization; chronic thromboembolic pulmonary hypertension; Doppler echocardiography; HIV; idiopathic pulmonary arterial hypertension; genetics; method; pulmonary arterial hypertension; scleroderma Abbreviations: ALK1 � activin receptor-like kinase 1; BMPR2� bone morphogenetic protein receptor II; CTEPH� chronic thromboembolic pulmonary hypertension; CXR� chest radiograph; Dlco� diffusing capacity of the lung for carbon monoxide; DT� deceleration time; FPAH� familial pulmonary arterial hypertension; HHT� hereditary hemorrhagic telangiectasia; IPAH� idiopathic pulmonary arterial hypertension; mPAP� mean pulmonary arterial pressure; NIH� National Institutes of Health; NYHA� New York Heart Association; PAH � pulmonary arterial hypertension; PH� pulmonary hypertension; RAP� right atrial pressure; RVET� right ventricular ejection time; RVSP� right ventricular systolic pressure; SLE� systemic lupus erythematosus; sPAP� systolic pulmonary arterial pressure; TR� tricuspid valve regurgitation; V˙co2 � carbon dioxide output; V˙e � minute ventilation; V˙/Q˙ � ventilation/perfusion; V˙o2 � oxygen consumption T his chapter reviews early detection, diagnosis,and screening of patients at risk for pulmonary arterial hypertension (PAH). We performed a com- prehensive review of published studies to provide an evidence-based analysis, including an assessment of the sensitivity and specificity of the methods used clinically to detect and diagnose PAH. Each of the diagnostic methods and strategies are examined, including those that are utilized for the confirmation of conditions associated with PAH. Novel diagnostic techniques and future directions for the field are then considered to complete this chapter. The sum- mary evidence tables can be viewed on-line at http://www.chestjournal.org/content/vol126/1_suppl/. Substantial technical progress has occurred for many of the diagnostic methods discussed, primarily those methods that assess cardiac structure or esti- mate pulmonary artery pressures. Since PAH does not become manifest until the pulmonary vascular disease is advanced, even mild elevations in pulmo- nary arterial pressure reflect diffuse and extensive vascular damage. Changes in right ventricular func- tion and structure, which can be assessed by nonin- vasive diagnostic methods, occur even later in the clinical course of PAH. Accordingly, there is a need for the development of an early detection approach that will require the identification and validation of biomarkers or other noninvasive and easily obtain- *From Mayo Clinic (Dr. McGoon), Rochester, Medical College of Wisconsin (Dr. Gutterman), Madison, WI; Georgetown University (Dr. Steen), Washington, DC; Columbia University College of Physicians and Surgeons (Dr. Barst), New York, NY; Center for Clinical Health Policy Research (Dr. McCrory), Department of Medicine, Duke University Medical Center, Center for Health Services Research in Primary Care; Department of Medicine (Dr. Fortin), Duke University Medical Center, Durham, NC; and Divi- sion of Allergy, Pulmonary and Critical Care (Dr. Loyd), Vanderbilt University School of Medicine, Nashville, TN. For financial disclosure information see page 1S. Reproduction of this article is prohibited without written permis- sion from the American College of Chest Physicians (e-mail: permissions@chestnet.org). Correspondence to: David Gutterman, MD, FCCP, CC-111 M/Medicine, VA Medical Center, 5000 W National Ave, Milwau- kee, WI 53295; e-mail: dgutt@mcw.edu 14S Pulmonary Arterial Hypertension: ACCP Guidelines © 2004 American College of Chest Physicians by guest on August 24, 2011chestjournal.chestpubs.orgDownloaded from able parameters to assess the intrinsic vascular pro- cess at a presymptomatic or early symptomatic stage. Historical Perspective The development of cardiac catheterization provided the first method to diagnose and confirm PAH, and was the pivotal diagnostic method for 3 decades after the first clinical description of idiopathic PAH (IPAH) in the early 1950s. Although cardiac catheterization is still necessary for disease confirmation in patients with suspected pulmonary hypertension (PH), in the cur- rent era it rarely reveals unsuspected new findings. The technical advances in noninvasive thoracic and cardiac imaging over the recent few decades enable the physi- cian to strongly suggest a diagnosis of PH before confirmation by cardiac catheterization. Echocardiography with Doppler ultrasound is the most portable and widely available technology among the noninvasive imaging methods. Echocar- diography provides both estimates of pulmonary artery pressure and an assessment of cardiac struc- ture and function. These features justify its applica- tion as the most commonly used screening tool in patients with suspected PAH. Evaluation of PAH Assessment of PAH is based on a logical sequence of determining whether there is a risk of PAH being present, whether PAH is likely to be present based on initial, noninvasive evaluation, clarifying the underlying etiology of PAH in an individual patient, and delineat- ing the specific hemodynamic profile, including the acute response to vasodilator testing. The schema for patient evaluation using this approach is provided in Figure 1, and is expanded in the text. Genetic Screening for Mutations That Cause PAH Mutations in the bone morphogenetic protein receptor II (BMPR2) gene have been identified in approximately 50% of patients with familial PAH (FPAH)1,2 and 25% of patients thought to have sporadic IPAH.3 Other FPAH families demonstrate linkage to the same chromosomal region, 2q32, where BMPR2 resides, but the responsible muta- tions have not been identified. Confirmation of linkage of any FPAH locus, other than 2q32, has not been reported to date. FPAH is inherited in an autosomal dominant manner with incomplete pen- etrance. Since penetrance may be as low as 10 to 20%, most individuals with the mutation never ac- quire the disease although they may still transmit the mutation to their progeny. In FPAH families, the siblings or children of FPAH patients or of obligate heterozygotes have an overall risk of 50% of inher- iting the gene, with a 20% penetrance, yielding an estimated risk of 10% of acquiring the disease. The age of onset of FPAH is broad, ranging from 1 to 74 years. There is an unexplained tendency for FPAH to develop at earlier ages in subsequent generations, a phenomenon termed genetic anticipation. This appears to have a biological basis (yet undiscovered), rather than being the result of ascertainment bias.4 The process of testing and counseling individuals for genetic mutations should be performed as part of a comprehensive program that includes discussion of the risks, benefits, and limitations of the test results. For genetic testing and counseling, molecular testing for the mutation should only be performed in a clinically approved and certified molecular genetics laboratory (Clinical Laboratory Improvement Act 1988 certified). The molecular confirmation of the mutation and testing of specific asymptomatic individuals is usually performed in FPAH families in whom a specific BMPR2 mutation has been previously identified. If the mutation creates or deletes a recognition site for a restriction enzyme, then a polymerase chain reac- tion test will determine whether or not individuals in that family harbor the mutation. If the individual does not have the mutation, the risk of FPAH is no different from the general population. A subject who possesses the mutation has a 10 to 20% lifetime risk of acquiring FPAH. Linkage Analysis Linkage analysis may clarify the genetic status of at-risk relatives for families in whom a specific BMPR2 mutation has not been identified. Samples from multi- ple family members, including at least two affected individuals from different generations, are necessary to perform linkage analysis. The accuracy of linkage anal- ysis can be� 99%, and is dependent on the location of informative genetic markers in the patient’s family and the accuracy of the clinical diagnosis of FPAH in affected family members. Linkage analysis should be used with caution unless the specific family is large enough to be genetically informative and the BMPR2 marker alleles can be shown to cosegregate with the FPAH phenotype in that family. Genetic counseling for family members at risk for FPAH is complicated due to decreased penetrance, variable age of onset, and inher- ent limitations of linkage studies. Gene Sequencing Mutations causing FPAH have been identified in all but 1 of 13 exons among the 130,000 bases that www.chestjournal.org CHEST / 126 / 1 / JULY, 2004 SUPPLEMENT 15S © 2004 American College of Chest Physicians by guest on August 24, 2011chestjournal.chestpubs.orgDownloaded from comprise BMPR2. When the mutation in a specific FPAH family is not known and the specimens available from that family are insufficient to conduct linkage, sequencing of the entire coding region is possible, but requires sequencing of several thou- sand bases. It is informative only if a functional mutation is identified. Prenatal Testing Prenatal testing for FPAH has not been reported, but it is feasible using mutational analysis or linkage in at-risk pregnancies, if the disease-causing muta- tion has been identified in affected family members, or if linkage has been established in a large geneti- Figure 1. Schema for patient evaluation. Hx� history; Echo� echocardiography; LH� left heart; CHD� congenital heart disease; CTD� connective tissue disease; PFT� pulmonary function test; TRV� peak velocity of TR jet; RVE � right ventricular enlargement; RAE� right atrial enlargement; RV � right ventricular; Dx� diagnosis; LV� left ventricular; R&LHC� right and left heart cathe- terization; RHC� right heart catheterization; PE� pulmonary embolism; a/c� anticoagulation; LA � left atrial; PCWP � pulmonary capillary wedge pressure; CO� cardiac output; PVR� pulmo- nary vascular resistance; Svo2 � mixed venous oxygen saturation. 16S Pulmonary Arterial Hypertension: ACCP Guidelines © 2004 American College of Chest Physicians by guest on August 24, 2011chestjournal.chestpubs.orgDownloaded from cally informative family prior to prenatal testing. Prenatal testing is controversial, especially for con- ditions such as FPAH that do not affect intellect and have effective treatments. Differences in perspective may exist among medical professionals and families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is needed. Genetic Testing in Families of Patients With Sporadic IPAH Because the identification of a genetic mutation in a patient with IPAH has significant implications for all bloodline relatives, molecular testing for muta- tions may soon become a “standard of care.” At present, however, only a positive result is informa- tive, since a negative test finding for mutations in a sporadic patient has limited value. The value of genetic testing in sporadic IPAH families will likely increase as additional mutations linked to familial IPAH are identified. Hereditary hemorrhagic telangiectasia (HHT) is a condition associated with mucocutaneous telangiec- tases causing recurrent epistaxis and GI bleeding, and arteriovenous malformations of the pulmonary, hepatic, and cerebral circulations. Pulmonary arte- riovenous malformations can cause significant right- to-left shunts leading to systemic hypoxemia, para- doxical embolism, stroke, and cerebral abscesses, and reduced pulmonary vascular resistance. How- ever, pulmonary hypertension has also been reported to occur in some individuals with HHT. Heteroge- neous defects in components of the transforming growth factor-� receptor complex, including endog- lin and activin receptor-like kinase 1 (ALK1) have been implicated in the autosomal dominant vascular dysplasia of HHT.5 Five families with HHT were identified with coexistent probands with FPAH, each with unique ALK1 mutations.6 It is not known whether specific mutations are responsible for both HHT and FPAH, or whether more complex genetic and environmental interactions facilitate the devel- opment of FPAH in individuals with ALK 1 muta- tions. The clinical role for genetic testing for ALK1 mutations in patients or families with HHT and FPAH has not yet been determined. Recommendations 1. Genetic testing and professional genetic counseling should be offered to relatives of patients with FPAH. Level of evidence: expert opinion; benefit: intermediate; grade of recommendation: E/A. 2. Patients with IPAH should be advised about the availability of genetic testing and counseling for their relatives. Level of evidence: expert opinion; benefit: intermedi- ate; grade of recommendation: E/A. Echocardiographic Screening of Asymptomatic Subjects at Risk for PAH Few reports have evaluated echocardiography for screening asymptomatic patients with PAH, since the incidence of disease is low and Bayesian analysis would predict a large number of false-positive test results. Furthermore, health insurers may not reim- burse the expense of testing “asymptomatic” individ- uals. Finally, whether establishing an early diagnosis of PAH (such as in a presymptomatic phase of FPAH) improves outcome is unknown, although it unquestionably has important emotional and social implications. In some individuals, pulmonary artery pressure may be normal at rest but increase to abnormally high levels during conditions of increased blood flow such as during exercise. The significance of this response is not clear: it may reflect an early phase of the development of overt disease or may indicate a chronic, but stable pulmonary circulatory functional limitation. A false-positive result due to measure- ment error caused by large swings in intrathoracic pressure during exercise might also be contributory. Exercise echocardiography to detect asymptomatic gene carriers was reported to have a sensitivity of 87.5% and specificity of 100% in two large German families with FPAH,7 but independent confirmation of these studies is not available. Clinical History Presenting Symptoms Patients with PAH generally present with a spec- trum of symptoms attributable to impaired oxygen transport and reduced cardiac output. Although PAH may be asymptomatic, particularly in its early stages, exertional dyspnea is the most frequent pre- senting symptom, and was present in 60% of patients in the National Institutes of Health (NIH) prospec- tive cohort study of patients with PPH.8 Dyspnea is eventually present in virtually all patients as the disease progresses. Fatigue, weakness, or complaints of general exertion intolerance are also common complaints. As PAH progresses, dyspnea may be present at rest. Anginal chest pain or syncope are each reported by approximately 40% of patients during the course of the disease.8 Since the symp- www.chestjournal.org CHEST / 126 / 1 / JULY, 2004 SUPPLEMENT 17S © 2004 American College of Chest Physicians by guest on August 24, 2011chestjournal.chestpubs.orgDownloaded from toms of PH are nonspecific, the initial evaluation of patients with these symptoms is often appropriately directed at diagnosing or excluding more common conditions. In the absence of an identifiable expla- nation, however, pulmonary vascular disease should be considered as a cause for these symptoms, par- ticularly unexplained dyspnea. Symptoms of Related Conditions Since PH may be associated with a variety of comorbid conditions, symptomatic evidence of a related illness should be considered. Orthopnea and paroxysmal nocturnal dyspnea suggest elevated pul- monary venous pressure and pulmonary congestion due to left-sided cardiac disease. Raynaud phenom- enon, arthralgias, or swollen hands and other symp- toms of connective tissue disease in the setting of dyspnea should raise the possibility of PAH related to connective tissue disease. A history of snoring or apnea provided by the patient’s partner warrants evaluation for sleep-disordered breathing as a poten- tial causative or contributory factor. Symptoms of Disease Progression Leg swelling, abdominal bloating and distension, anorexia, plethora, and more profound fatigue de- velop as right ventricular dysfunction and tricuspid valve regurgitation (TR) evolve. A qualitative assess- ment of activity tolerance is useful in monitoring disease progression and response to treatment. The World Health Organization classification of func- tional capacity,9 an adaptation of the New York Heart Association (NYHA) system, has been useful in this regard (Table 1). Family and Personal Medical History Because of the recognized genetic component of PAH, inquiry into whether other family members have had symptoms or an established diagnosis of PAH or a history of connective tissue disease may lead to early recognition of clinical disease. Potential toxic exposures should be explored, such as a history of use of appetite suppressants, toxic rapeseed oil, or chemotherapeutic agents (including mitomycin-C, carmustine, etoposide, cyclophosphamide, or bleo- mycin). Known or suspected exposure to HIV infec- tion should be explored. Although a history of pul- monary embolism or deep vein thrombosis in a patient with diagnosed or suspected PAH requires a meticulous search for unresolved chronic thromboem- bolic disease, chronic thromboembolic PH (CTEPH) may occur even in the absence of a recognized history of venous thromboembolism. Physical Examination Signs of PH on physical examination are subtle and often overlooked. Although no rigorous analysis of the sensitivity and speci