肥厚心肌病

ACC/ESC EXPERT CONSENSUS DOCUMENT American College of Cardiology/ European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines WRITING COMMITTEE MEMBERS BARRY J. MARON, MD, FACC, FESC, Co-Chair WILLIAM J. MCKENNA, MD, FACC, FESC,* Co-Chair GORDON K. DANIELSON, MD, FACC LUKAS J. KAPPENBERGER, MD, FACC, FESC* HORST J. KUHN, MD, FESC* CHRISTINE E. SEIDMAN, MD *Official representatives of the European Society of Cardiology PRAVIN M. SHAH, MD, MACC WILLIAM H. SPENCER, III, MD, FACC PAOLO SPIRITO, MD, FACC, FESC* FOLKERT J. TEN CATE, MD, PHD, FACC, FESC* E. DOUGLAS WIGLE, MD, FACC ACCF TASK FORCE ON CLINICAL EXPERT CONSENSUS DOCUMENTS MEMBERS ROBERT A. VOGEL, MD, FACC, Chair JONATHAN ABRAMS, MD, FACC ERIC R. BATES, MD, FACC BRUCE R. BRODIE, MD, FACC* PETER G. DANIAS, MD, PHD, FACC* GABRIEL GREGORATOS, MD, FACC MARK A. HLATKY, MD, FACC JUDITH S. HOCHMAN, MD, FACC *Former members of Task Force; †Former Chair of Task Force SANJIV KAUL, MBBS, FACC ROBERT C. LICHTENBERG, MD, FACC JONATHAN R. LINDNER, MD, FACC ROBERT A. O’ROURKE, MD, FACC† GERALD M. POHOST, MD, FACC RICHARD S. SCHOFIELD, MD, FACC CYNTHIA M. TRACY, MD, FACC* WILLIAM L. WINTERS, JR, MD, MACC* ESC COMMITTEE FOR PRACTICE GUIDELINES MEMBERS WERNER W. KLEIN, MD, FACC, FESC, Chair SILVIA G. PRIORI, MD, PHD, FESC, Co-Chair ANGELES ALONSO-GARCIA, MD, FACC, FESC CARINA BLOMSTRO¨M-LUNDQVIST, MD, PHD, FESC GUY DE BACKER, MD, PHD, FACC, FESC JAAP DECKERS, MD, FESC MARKUS FLATHER, MD, FESC JAROMIR HRADEC, MD, FESC ALI OTO, MD, FACC, FESC ALEXANDER PARKHOMENKO, MD, FESC SIGMUND SILBER, MD, PHD, FESC ADAM TORBICKI, MD, FESC TABLE OF CONTENTS Preamble........................................................................................2 Introduction ..................................................................................2 General Considerations and Perspectives .....................................2 Nomenclature, Definitions, and Clinical Diagnosis.....................3 Obstruction to LV Outflow..........................................................3 Genetics and Molecular Diagnosis ...............................................4 General Considerations for Natural History and Clinical Course ......................................................................6 When citing this document, the American College of Cardiology Foundation and the European Society of Cardiology would appreciate the following citation format: Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, Shah PM, Spencer WH, Spirito P, Ten Cate FJ, Wigle ED. ACC/ESC clinical expert consensus document on hypertrophic cardiomyopathy: a report of the Amer- ican College of Cardiology Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines (Committee to Develop an Expert Consensus Document on Hypertrophic Cardiomyopathy). J Am Coll Cardiol 2003;42:page-page. Copies: This document is available on the Web sites of the ACC at www.acc.org and ESC at www.escardio.org. Single copies of this document are available by calling 800-253-4636 (US only) or writing the American College of Cardiology Foundation, Resource Center, 9111 Old Georgetown Road, Bethesda, MD 20814-1699 as well as by calling or writing ESC Guidelines–Reprints, Elsevier Publishers Ltd., 32 James- town Road, London, NW17BY, United Kingdom (Tel: �44.207.424.4422; Fax: �44.207.424.4433; Email: gr.davies@elsevier.com. Journal of the American College of Cardiology Vol. 42, No. 9, 2003 © 2003 by the American College of Cardiology Foundation and the European Society of Cardiology ISSN 0735-1097/03/$30.00 Published by Elsevier Inc. doi:10.1016/S0735-1097(03)00941-0 Symptoms and Pharmacological Management Strategies ............7 Treatment Options for Drug-Refractory Patients .....................11 Additional Approaches to Relieve Outflow Obstruction and Symptoms.............................................................................12 Sudden Cardiac Death................................................................16 Atrial Fibrillation ........................................................................20 PREAMBLE This document has been developed as a Clinical Expert Consensus Document (CECD), combining the resources of the American College of Cardiology Foundation (ACCF) and the European Society of Cardiology (ESC). It is intended to provide a perspective on the current state of management of patients with hypertrophic cardiomyopathy. Clinical Expert Consensus Documents are intended to inform practitioners, payers, and other interested parties of the opinion of the ACCF and the ESC concerning evolving areas of clinical practice and/or technologies that are widely available or new to the practice community. Topics chosen for coverage by expert consensus documents are so designed because the evidence base, the experience with technology, and/or the clinical practice are not considered sufficiently well developed to be evaluated by the formal American College of Cardiology/American Heart Association (ACC/ AHA) Practice Guidelines process. Often the topic is the subject of considerable ongoing investigation. Thus, the reader should view the CECD as the best attempt of the ACC and the ESC to inform and guide clinical practice in areas where rigorous evidence may not yet be available or the evidence to date is not widely accepted. When feasible, CECDs include indications or contraindications. Some topics covered by CECDs will be addressed subsequently by the ACC/AHA Practice Guidelines Committee. The Task Force on Clinical Expert Consensus Docu- ments makes every effort to avoid any actual or potential conflicts of interest that might arise as a result of an outside relationship or personal interest of a member of the writing panel. Specifically, all members of the writing panel are asked to provide disclosure statements of all such relation- ships that might be perceived as real or potential conflicts of interest to inform the writing effort. These statements are reviewed by the parent task force, reported orally to all members of the writing panel at the first meeting, and updated as changes occur. Robert A. Vogel, MD, FACC Chair, ACCF Task Force on Clinical Expert Consensus Documents Werner W. Klein, MD, FACC, FESC Chair, ESC Committee for Practice Guidelines INTRODUCTION Organization of committee and evidence review. The Writing Committee consisted of acknowledged experts in hypertrophic cardiomyopathy (HCM) representing the American College of Cardiology Foundation and the Eu- ropean Society of Cardiology. Both the academic and private practice sectors were represented. The document was reviewed by 2 official reviewers nominated by the ACCF, 3 official reviewers nominated by the ESC, 12 members of the ACCF Clinical Electrophysiology Committee, and 4 addi- tional content reviewers nominated by the Writing Com- mittee. The document was approved for publication by the ACCF Board of Trustees in August 2003 and the Board of ESC in July 2003. This document will be considered current until the Task Force on Clinical Expert Consensus Docu- ments revises or withdraws it from distribution. In addition to the references cited as part of this document, a compre- hensive bibliography including relevant, supplementary ref- erences is available on the ACCF and ESC websites. Purpose of this Expert Consensus Document. Hypertro- phic cardiomyopathy is a complex and relatively common genetic cardiac disorder (about 1:500 in the general adult population) (1) that has been the subject of intense scrutiny and investigation for over 40 years (2–15). Hypertrophic cardiomyopathy affects men and women equally and occurs in many races and countries, although it appears to be under-diagnosed in women, minorities, and under-served populations (16–20). Hypertrophic cardiomyopathy is a particularly common cause of sudden cardiac death (SCD) in young people (including trained athletes) (21–29) and may cause death and disability in patients of all ages, although it is also frequently compatible with normal longevity (30–35). Be- cause of its heterogeneous clinical course and expression (7,36–42), HCM frequently presents uncertainty and rep- resents a management dilemma to cardiovascular specialists and other practitioners, particularly those infrequently en- gaged in the evaluation of patients with this disease. Furthermore, with the recent introduction of novel treat- ment strategies targeting subgroups of patients with HCM (7,43–49), controversy is predictable, and difficult questions periodically arise. Consequently, it is now particularly timely to clarify and place into perspective those clinical issues relevant to the rapidly evolving management for HCM. GENERAL CONSIDERATIONS AND PERSPECTIVES This clinical scientific statement represents the consensus of a panel of experts appointed by the ACC and ESC. The writing group is comprised of cardiovascular specialists and molecular biologists, each having extensive experience with HCM. The panel focused largely on the management of this complex disease and derived prudent, practical, and contemporary treatment strategies for the many subgroups of patients comprising the broad HCM disease spectrum. Because of the relatively low prevalence of HCM in general cardiologic practice (50), its diverse presentation, and mech- anisms of death and disability and skewed patterns of patient referral (7,11,13,36–38,42,51–59), the level of evi- 2 Maron and McKenna et al. JACC Vol. 42, No. 9, 2003 ACC/ESC Expert Consensus Document on Hypertrophic Cardiomyopathy November 5, 2003:000–000 dence governing management decisions for drugs or devices has often been derived from non-randomized and retrospec- tive investigations. Large-scale controlled and randomized study designs, such as those that have provided important answers regarding the management of coronary artery dis- ease (CAD) and congestive heart failure (60–62), have generally not been available in HCM as a result of these factors. Therefore, treatment strategies have necessarily evolved based on available data that have frequently been observational in design, sometimes obtained in relatively small patient groups, or derived from the accumulated clinical experience of individual investigators, and reason- able inferences drawn from other cardiac diseases. Conse- quently, the construction of strict clinical algorithms de- signed to assess prognosis and dictate treatment decisions for all patients has been challenging and has not yet achieved general agreement. In some clinical situations, management decisions and strategies unavoidably must be individualized to the particular patient. Understanding of the molecular basis, clinical course, and treatment of HCM has increased substantially in the last decade. In particular, there has been a growing awareness of the clinical and molecular heterogeneity characteristic of this disorder and the many patient subgroups that inevitably influence considerations for treatment. Some of these man- agement strategies are novel and evolving, and this docu- ment cannot, in all instances, convey definitive assessments of their role in the treatment armamentarium. Also, for some uncommon subsets within the broad disease spectrum, there are little data currently available to definitively guide therapy. With these considerations in mind, the panel has aspired to create a document that is not only current and pertinent but also has the potential to remain relevant for many years. NOMENCLATURE, DEFINITIONS, AND CLINICAL DIAGNOSIS The clinical diagnosis of HCM is established most easily and reliably with two-dimensional echocardiography by demonstrating left ventricular hypertrophy (LVH) (typically asymmetric in distribution, and showing virtually any diffuse or segmental pattern of left ventricular [LV] wall thicken- ing) (36). Left ventricular wall thickening is associated with a nondilated and hyperdynamic chamber (often with systolic cavity obliteration) in the absence of another cardiac or systemic disease (e.g., hypertension or aortic stenosis) capa- ble of producing the magnitude of hypertrophy evident, and independent of whether or not LV outflow obstruction is present (1,5,7,36). Although the usual clinical diagnostic criteria for HCM is a maximal LV wall thickness greater than or equal to 15 mm, genotype-phenotype correlations have shown that virtually any wall thickness (including those within normal range) are compatible with the presence of a HCM mutant gene (6,17,19,63–65). Mildly increased LV wall thicknesses of 13 to 14 mm potentially due to HCM should be distinguished from certain extreme expressions of the physiologically-based athlete’s heart (66–68). The ad- vent of contemporary magnetic resonance imaging that provides high-resolution tomographic images of the entire LV may represent an additional diagnostic modality (69) particularly in the presence of technically suboptimal echo- cardiographic studies or when segmental hypertrophy is confined to unusual locations within the LV wall. Since the modern description by Teare in 1958 (12), HCM has been known by a confusing array of names that largely reflect its clinical heterogeneity, relatively uncom- mon occurrence in cardiologic practice, and the skewed experience of early investigators. This problem in nomen- clature has been an obstacle to general recognition of the disease within the medical and non-medical community. Hypertrophic cardiomyopathy (or HCM) is now widely accepted as the preferred term (7) because it describes the overall disease spectrum without introducing misleading inferences that LV outflow tract obstruction is an invariable feature of the disease, such as is the case with hypertrophic obstructive cardiomyopathy (70), muscular subaortic steno- sis (71), or idiopathic hypertrophic subaortic stenosis (72). Indeed, most patients with HCM do not demonstrate outflow obstruction under resting (basal) conditions, al- though many may develop dynamic subaortic gradients of varying magnitude with provocative maneuvers or agents (7,13,41,72–77). Of note, even though the absence of obstruction (at rest) is common, both in patients with and without symptoms, most treatment modalities have targeted those symptomatic HCM patients with outflow obstruction (41,43–49,78–108). OBSTRUCTION TO LV OUTFLOW It is of clinical importance to distinguish between the obstructive or nonobstructive forms of HCM, based on the presence or absence of a LV outflow gradient under resting and/or provocable conditions (5,7,11,13,41,109,110). In- deed, in most patients, management strategies have tradi- tionally been tailored to the hemodynamic state. Outflow gradients are responsible for a loud apical systolic ejection murmur associated with a constellation of unique clinical signs (14,72,111), hypertrophy of the basal portion of ventricular septum and small outflow tract, and an enlarged and elongated mitral valve in many patients (39,112–114). Obstruction may either be subaortic (13,71,72) or mid- cavity (13,115) in location. Subaortic obstruction is caused by systolic anterior motion (SAM) of the mitral valve leaflets and mid-systolic contact with the ventricular septum (13,71,113,116–119). This mechanical impedance to out- flow occurs in the presence of high velocity ejection in which a variable proportion of the forward blood flow may be ejected early in systole (120,121). Systolic anterior motion is probably attributable to a drag effect (117,122) or possibly a Venturi phenomenon (13,118) and is responsible not only for subaortic obstruction, but also the concomitant 3JACC Vol. 42, No. 9, 2003 Maron and McKenna et al. November 5, 2003:000–000 ACC/ESC Expert Consensus Document on Hypertrophic Cardiomyopathy mitral regurgitation (usually mild-to-moderate in degree) due to incomplete leaflet apposition, which is typically directed posteriorly into the left atrium (111,123). When the mitral regurgitation jet is directed centrally or anteriorly into the left atrium, or if multiple jets are present, indepen- dent abnormalities intrinsic to the mitral valve should be suspected (e.g., myxomatous degeneration, mitral leaflet fibrosis, or anomalous papillary muscle insertion) (13,91,115,124). Occasionally (perhaps in 5% of cases), gradients and impeded outflow are caused predominately by muscular apposition in the mid-cavity region—usually in the absence of mitral-septal contact—involving anomalous direct insertion of anterolateral papillary muscle into the anterior mitral leaflet, or excessive mid-ventricular or pap- illary muscle hypertrophy and malalignment (13,91,115). Although it has previously been subject to periodic controversy (72,120,125,126), there is now widespread rec- ognition that the subaortic gradient (30 mm Hg or more) and associated elevations in intra-cavity LV pressure reflect true mechanical impedance to outflow and are of patho- physiologic and prognostic importance to patients with HCM (127,128). Indeed, outflow obstruction is a strong, independent predictor of disease progression to HCM- related death (relative risk vs. nonobstructed patients, 2.0), to severe symptoms of New York Heart Association (NYHA) class III or IV, and to death due specifically to heart failure and stroke (relative risk vs. nonobstructed patients, 4.4) (127). However, the likelihood of severe symptoms and death from outflow tract obstruction was not greater when the gradient was increased in magnitude above the threshold of 30 mm Hg (127). Disease consequences related to chronic outflow gradi- ents are likely to be mediated by the resultant increase in LV wall stress, myocardial ischemia and eventually cell death and replacement fibrosis (7,127,129). Therefore, the pres- ence of LV outflow obstruction justifies intervention to reduce or abolish significant subaortic gradients in severely symptomatic patients who are refractory to maximum med- ical management (11,14,41,127). Obstruction in HCM is characteristically dynamic (i.e., not fixed): the magnitude (or even presence) of an outflow gradient may be spontaneously labile and vary considerably with a number of physiologic alterations as diverse as a heavy meal or ingestion of a small amount of alcohol (72,73,109). Different gradient cut-offs have been proposed for segregating individual patients into hemodynamic sub- groups, but rigorous partitioning into such hemodynamic categories according to gradient can be difficult because of the unpredictable dynamic changes that may occur in individual patients (72,73). Nevertheless, it is reasonable to divide the overall HCM disease spectrum into hemodynamic subgroups, based on the representative peak instantaneous gradient as assessed with continuous wave Doppler: 1) obstructive gradient under basal (resting) conditions equal to or greater than 30 mm Hg (2.7 m/s by Doppler), 2) latent (provocable) obstructive—gradient less than 30 mm Hg under basal conditions and equal to or greater than 30 mm Hg with provocation, and 3) nonobstructive—less than 30 mm Hg under both basal and (provocable) conditions. By current clinical convention, LV outflow gradients are routinely measured noninvasively with continuous wave Doppler echocardiography, generally obviating the need for serial cardiac catheterizations in this disease (except when athero- sclerotic CAD or other associated anomalies such as intrin- sic valvular disease are suspected). It is important to underscore that a variety of interven- tions have been traditionally employed to elicit latent (inducible) gradients in the echocardiography, cardiac cath- eterization, and exercise laboratories (i.e