Guidelines for Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy (JCS 2012) – Digest Version – JCS Joint Working Group

Circulation Journal JCS GUIDELINES Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Guidelines for Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy (JCS 2012) – Digest Version – JCS Joint Working Group

Table of Contents Introduction to the Revised Guidelines∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 753 III Treatment ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 763 I Pathophysiology∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 754 1. Management of Daily Life∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 763 1. Definition and Basic Pathophysiology∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 754 2. Pharmacotherapy∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 763 2. Causes of Hypertrophic Cardiomyopathy∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 756 3. Non-Pharmacotherapy∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 766 3. Pathophysiology and Hemodynamics∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 757 4. Management and Treatment of Hypertrophic 4. Prognosis∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 757 Cardiomyopathy in Children∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 769 II Diagnosis∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 757 References∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 769 1. Symptoms and Physical Findings∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 758 Appendix∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 773 2. Evaluation Method∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 758 3. Diagnostic Flow Charts∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 761 (Circ J 2016; 80: 753 – 774) 4. Diagnosis of Hypertrophic Cardiomyopathy in Children∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ 762

Introduction to the Revised Guidelines

The diagnosis and treatment of hypertrophic cardiomyopathy accumulated consistently for 10 years since the release of the (HCM) require special expertise. Physicians often encounter first edition of this guideline document. A number of new this disease in clinical practice, but there are few randomized genetic mutations associated with HCM have been reported. clinical studies on the diagnosis and treatment of this disease, Physicians are becoming increasingly aware of the importance especially that on optimal treatment options. In 2002, The of differentiating HCM from other conditions such as Fabry Japanese Circulation Society published the “Guidelines for disease that may cause HCM-like cardiac hypertrophy but Diagnosis and Treatment of Patients with Hypertrophic Car- requiring different treatment. The clinical use of diagnostic diomyopathy” (Chair: Junichi Yoshikawa). In 2007, the guide- imaging techniques especially cardiac magnetic resonance lines were revised to add new findings obtained during the five imaging (MRI) has become common, and physicians under- years after the launch of the first edition (Chair: Yoshinori stand better the clinical significance of late gadolinium en- Doi), and the second edition was used widely in clinical prac- hancement (LGE) on contrast-enhanced MRI. New findings tice. During the five years after the release of the second edi- have also been obtained for risk factors in high-risk patients. tion, the American College of Cardiology Foundation (ACCF)/ In the present revision, a section on device therapy is newly the American Heart Association (AHA) and the European added to the chapter on non-pharmacotherapy to describe Society of Cardiology (ESC) provided new guidelines on the implantable cardioverter-defibrillators (ICDs) and cardiac re- diagnosis and treatment of cardiomyopathies. We decided to synchronization therapy (CRT) in addition to the descriptions revise the guidelines to reconfirm the definition of HCM and on pacemaker therapy in the previous versions. Data on the add new findings. mid- and long-term outcome of percutaneous transluminal Since few randomized clinical studies are available for the septal myocardial ablation (PTSMA) are added in this revi- diagnosis and treatment of HCM, not only data in Japan but sion. In the present revision of the guidelines, members of the also those in Western countries were referred in this revision expert committee discussed in depth, and independent assess- as in the previous ones. However, new clinical data have been ment committee members provided comments to make the

Released online February 3, 2016 Mailing address: Scientific Committee of the Japanese Circulation Society, 18F Imperial Hotel Tower, 1-1-1 Uchisaiwai-cho, Chiyoda-ku, Tokyo 100-0011, Japan. E-mail: [email protected] This English language document is a revised digest version of Guidelines for Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy reported at the Japanese Circulation Society Joint Working Groups performed in 2011 (Website: http://www.j-circ. or.jp/guideline/pdf/JCS2012_doi_d.pdf). Joint Working Groups: The Japanese Circulation Society, The Japanese Association for Thoracic Surgery, The Japanese Society of Pediat- ric Cardiology and Cardiac Surgery, Japanese Association of Cardiovascular Intervention and Therapeutics, Japanese Society for Car- diovascular Surgery, The Japanese College of Cardiology, The Japanese Society of Electrocardiology ISSN-1346-9843 doi: 10.1253/circj.CJ-66-0122 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Circulation Journal Vol.80, March 2016 754 JCS Joint Working Group guidelines useful in clinical practice. We hope these guide- [Abbreviations] lines will help clinicians treat patients with HCM. ACCF: American College of Cardiology Foundation In this document, recommendations for the diagnosis and ACE: angiotensin-converting enzyme treatment of HCM are described with their classification of AHA: American Heart Association recommendations and level of evidence grade. Classification AMP: adenosine monophosphate of Recommendations and Level of Evidence are as follows: ARB: angiotensin receptor blocker CRT: cardiac resynchronization therapy Classification of Recommendations CT: computed tomography Class I: There is evidence and/or general agreement that a DDD: dual-chamber, dual-pacing, dual-response given procedure or treatment is useful and effective. D-HCM: dilated phase of hypertrophic cardiomyopathy Class II: There is conflicting evidence and/or a divergence of ECG: electrocardiography opinion about the usefulness/efficacy of a procedure ESC: European Society of Cardiology or treatment. FDG-PET: fluorodeoxyglucose positron emission tomography Class IIa: Weight of evidence and data and opinion is in HCM: hypertrophic cardiomyopathy favor of usefulness and/or effectiveness. HOCM: hypertrophic obstructive cardiomyopathy Class IIb: Usefulness/efficacy is less well established by ICD: implantable cardioverter-defibrillator evidence/opinion. LGE: late gadolinium enhancement Class III: There is evidence and/or general agreement that the LVEF: left ventricular ejection fraction procedure/treatment is not useful/effective, and in LVOT: left ventricular outflow tract some cases may be harmful. MHLW: Ministry of Health, Labor and Welfare MR: mitral regurgitation Level of Evidence MRI: magnetic resonance imaging Level A: Data derived from multiple randomized clinical NYHA: New York Heart Association studies or meta-analyses. PTSMA: percutaneous transluminal septal myocardial ablation Level B: Data derived from a single randomized study or QOL: quality of life large-scale non-randomized studies. RI: radioactive isotope Level C: Only consensus opinion of experts and/or small-size SAM: systolic anterior motion clinical studies (including retrospective studies and WHO/ISFC: World Health Organization/International Soci- registries). ety and Federation of Cardiology

I Pathophysiology

1. Definition and Basic Pathophysiology include ischemic, valvular, hypertensive, inflammatory (myocarditis) and metabolic cardiomyopathies, sensitivity and toxic reactions, peripartum cardiomyopathy, and general system 1. Definition and Classification disease including neuromuscular disorders, and connective Clinically, cardiomyopathies are defined as a group of dis- tissue disorders. eases of the myocardium associated with cardiac dysfunction In 2006, the AHA proposed a new definition and classifica- where no other causes such as valvular disease and hyperten- tion of cardiomyopathies.9 The AHA defined cardiomyopa- sion are present.1–4 Hypertrophic cardiomyopathy is defined thies as a “heterogeneous group of diseases of the myocardi- by an increase in the thickness of the left or right ventricular um associated with mechanical and/or electrical dysfunction wall or of both walls.5–7 that usually (but not invariably) exhibit inappropriate ven- In the report of the World Health Organization/Interna- tricular hypertrophy or dilatation and are due to a variety of tional Society and Federation of Cardiology (WHO/ISFC) causes that frequently are genetic.” In 2008, the ESC revised Task Force on the Definition and Classification of Cardiomy- the WHO/ISFC classification to define a cardiomyopathy as opathies published in 1980,8 cardiomyopathies are defined as “heart muscle diseases of unknown cause.” However, with advanced research and characterization of causative genes and abnormal sarcomere proteins, WHO/ISFC revised the defini- Table 1. Definition and Classification of Cardiomyopathies tion by deleting the expression of “unknown cause” to “dis- by the 1995 WHO/ISFC Task Force 1 eases of the myocardium associated with cardiac dysfunction.” Definition: It is expected that cardiomyopathies will be classified by Cardiomyopathies are defined as diseases of the myocardium cause when further studies clarify the causes of the disease in associated with cardiac dysfunction. detail. As the classification based on clinical manifestations Classification: has been commonly used, the 1995 WHO/ISFC report kept 1. Dilated cardiomyopathy (DCM) the long-established categories of dilated, hypertrophic and 2. Hypertrophic cardiomyopahy (HCM) restrictive cardiomyopathies, and add new categories of arrhythmogenic right ventricular cardiomyopathy, and unclassi- 3. Restrictive cardiomyopathy (RCM) fied cardiomyopathies (Table 1).1 4. Arrhythmogenic right ventricular cardiomyopathy The 1995 WHO/ISFC report uses specific cardiomyopathies 5. Unclassified cardiomyopathy to describe “heart muscle diseases that are associated with Specific cardiomyopathies specific cardiac or systemic disorders,” and no longer uses the WHO/ ISFC, World Health Organization/International Society term “secondary cardiomyopathies.” Specific cardiomyopathies and Federation of Cardiology.

Circulation Journal Vol.80, March 2016 JCS Guidelines for Diagnosis and Treatment of Patients With HCM 755

Table 2. HCM and Diseases With HCM-Like Manifestations HCM: Diseases with HCM-like manifestations: Myofilament protein mutations (See Table 4) Familial diseases (See Tables 5 and 6) β-Myosin heavy chain Glycogen storage disease Cardiac myosin-binding protein C e.g., Pompe disease, PRKAG2 mutation, Forbes’ disease, and Danon disease Cardiac troponin I Lysosomal diseases Cardiac troponin T e.g., Anderson-Fabry disease, and Hurler disease α-Tropomyosin Mitochondrial disease Essential myosin light chain Syndromes Regulatory myosin light chain Noonan syndrome α-Cardiac actin LEOPARD syndrome α-Myosin heavy chain Friedreich’s ataxia Titin Beckwith-Wiedemann syndrome Cardiac troponin C Swyer syndrome Muscle LIM protein Others Unknown causative genes Familial amyloidosis Nonfamilial diseases Obesity Infant of diabetic mother Athletes Amyloidosis HCM, hypertrophic cardiomyopathy.

Table 3. Pathophysiology of HCM Described by the MHLW Idiopathic Cardiomyopathy Research Group in 2005 Hypertrophic cardiomyopathies are diseases of the myocardium associated with left and/or right ventricular hypertrophy where no other causes are present, and are characterized by asymmetric cardiac hypertrophy. Typically, the left ventricle is not dilated, and the left ventricular contractile function is normal or increased. The essential pathophysiology of HCM is left ventricular diastolic dysfunction due to cardiac hypertrophy. (1) HCM with left ventricular outflow tract obstruction is called hypertrophic obstructive cardiomyopathy (HOCM). (2) There are hypertrophic cardiomyopathies affecting specific regions of the heart, such as midventricular obstruction (obstruction is located in the middle of the left ventricle) and apical hypertrophic cardiomyopathy (hypertrophy is located in the apex of left ventricle). (3) During the course of HCM, the thickened ventricular wall becomes thinner, and left ventricular contractile dysfunction associated with ventricular cavity dilatation may develop and lead to manifestations similar to dilated cardiomyopathy. This is called dilated phase of hypertrophic cardiomyopathy (D-HCM). The diagnosis of D-HCM is confirmed by observation of clinical course. In patients without detailed observation, the diagnosis may be made based on the prior and definite diagnosis as HCM. HCM, hypertrophic cardiomyopathy; MHLW, Ministry of Health, Labor and Welfare. Adapted from Research Group on Idiopathic Cardiomyopathy, Intractable Disease Research Project of the Japanese Ministry of Health, Labor and Welfare, Cardiomyopathy: Diagnostic guidelines and commentary, 2005.13

“a myocardial disorder in which the heart muscle is structur- to specific causes may respond well to specific treatment. ally and functionally abnormal, in the absence of coronary Table 2 lists several genes associated with HCM and diseases artery disease, hypertension, valvular disease and congenital with HCM-like manifestations. heart disease sufficient to cause the observed myocardial abnormality.”10 2. Basic Pathophysiology of HCM With the advancement of molecular genetics in recent In 2005, the idiopathic cardiomyopathy research group at the years, many genes associated with HCM have been identified, Ministry of Health, Labor and Welfare (MHLW) thoroughly and research has revealed that diverse factors are responsible revised their guidelines for the diagnosis of cardiomyopa- for the development of HCM. In the present guideline docu- thies.12,13 The research group defined the basic pathophysiol- ment, the definition of HCM as described in the 1995 WHO/ ogy of HCM as in Table 3. Since the pathophysiological ISFC report is used on the basis of the above-described pro- feature of HCM is left ventricular inflow dysfunction due to posals on cardiomyopathies by the AHA and ESC. Hypertro- abnormal left ventricular distension, HCM is defined as “left phic cardiomyopathy is defined as cardiomyopathies resulting ventricular diastolic dysfunction due to cardiac hypertrophy” from mutations in sarcomeric genes or other type of muta- in order to avoid confusing with restrictive cardiomyopathy. tions, and those not associated with any other storage disease In the past, HCM had been classified into obstructive and or systemic diseases affecting multiple organ systems on the non-obstructive HCM on the basis of the presence/absence of basis of all available evaluations. Cardiac hypertrophy result- left ventricular outflow tract (LVOT) gradient. However, as an ing from storage disease or systemic diseases affecting mul- essential pathophysiology of HCM is abnormal myocardial tiple organ systems is classified separately from HCM into hypertrophy, LVOT obstruction should be considered as one “diseases causing HCM-like manifestations.”11 Physicians of the manifestations resulted from abnormal myocardial hy- must be aware that patients with HCM-like manifestations due pertrophy. Accordingly, it is desirable that obstructive and

Circulation Journal Vol.80, March 2016 756 JCS Joint Working Group

Table 4. Causative Gene Mutations of HCM Gene Locus Protein Frequency (%) Myofilament/Sarcomeric HCM Giant filament TTN 2q31 Titin <1 Thick filament MYH7 14q11.2-q12 β-Myosin heavy chain 25~40 MYH6 14q11.2-q12 α-Myosin heavy chain <1 MYL2 12q23-q24.3 Regulatory myosin light chain <1 MYL3 3p21.2-p21.3 Essential myosin light chain <1 Intermediate filament MYBPC3 11p11.2 Cardiac myosin-binding protein C 25~40 Thin filament TNNT2 1q32 Cardiac troponin T 3~5 TNNI3 19p13.4 Cardiac troponin I 1~5 TPM1 15q22.1 α-Tropomyosin 1~5 ACTC 15q14 α-Cardiac actin <1 TNNC1 3p21.1 Cardiac troponin C <1 Z-disc HCM ACTN2 1q42-q43 α-Actinin 2 <1 ANKRD1 10q23.31 Cardiac ankyrin repeat protein <1 CSRP3 11p15.1 Muscle LIM protein <1 LDB3 10q22.2-q23.3 LIM binding domain 3 (cypher) 1~5 MYOZ2 4q26-q27 Myozenin 2 <1 TCAP 17q12-q21.1 Telethonin <1 VCL 10q22.1-q23 Vinculin/Metavinculin <1 Calcium-Handling HCM JPH2 20q13.12 Junctophilin 2 <1 PLN 6q22.1 Phospholamban <1 HCM, hypertrophic cardiomyopathy.

Table 5. Disease-Causing Genes of HCM-Like Manifestation Syndrome Gene Locus Protein Left ventricular noncompaction DTNA 18q12 α-Dystrobrevin Barth syndrome/Left ventricular noncompaction TAZ Xq28 Tafazzin (G4.5) Danon disease LAMP2 Xq24 Lysosome-associated membrane protein 2 Fabry disease GLA Xq22 α-Galactosidase A Forbes’ disease AGL 1p21 Amylo-1,6-glucosidase Friedrich’s ataxia FXN 9q13 Frataxin Noonan syndrome KRAS 12p12.1 v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog Noonan syndrome SOS1 2p22-p21 Son of sevenless homolog 1 Noonan syndrome, LEOPARD syndrome PTPN11 12q24.1 Protein tyrosine phosphatase, non-receptor type 11, SHP-2 Noonan syndrome, LEOPARD syndrome RAF1 3p25 V-RAF-1 murine leukemia viral oncogene homolog 1 Pompe disease GAA 17q25.2-q25.3 α–1,4-glucosidase deficiency Cardiac hypertrophy associated with WPW syndrome PRKAG2 7q35-q36.36 AMP-activated protein kinase HCM, hypertrophic cardiomyopathy; WPW, Wolff-Parkinson-White; AMP, adenosine monophosphate.

non-obstructive HCM be termed collectively as HCM, and HCM with LVOT obstruction be called hypertrophic obstruc- 2. Causes of Hypertrophic Cardiomyopathy tive cardiomyopathy (HOCM). There are HCM affecting specific regions of the heart, such as midventricular obstructive Hypertrophic cardiomyopathy has long been known to run in cardiomyopathy and apical hypertrophic cardiomyopathy. families. In 1990, a study on the cause of familial HCM using Hypertrophic cardiomyopathy presenting with features simu- molecular genetic techniques revealed families with myocar- lating dilated cardiomyopathy is described as dilated phase of dial β-myosin heavy chain gene mutations.16 In subsequent hypertrophic cardiomyopathy (D-HCM).14,15 studies, more than 900 distinct mutations in at least 16 genes

Circulation Journal Vol.80, March 2016 JCS Guidelines for Diagnosis and Treatment of Patients With HCM 757 were reported as causes of HCM. The cause of familial HCM gions with severe hypertrophy such as the LVOT and the mid has been detected in about 50~60% of HCM families. Table 4 ventricle.28,29 Abnormalities in coronary microcirculation may lists major causative genes of HCM, which shows autosomal lead to myocardial ischemia and reduced coronary flow re- dominant inheritance, and the frequency of mutations.17–19 serve, causing chest pain and other symptoms.30 Patients with mitochondrial diseases and Fabry disease, which are classified into specific cardiomyopathies, may present with HCM-like manifestations. Mutations in adenosine monophos- 4. Prognosis phate (AMP)-activated protein kinase may cause glycogen storage disease presenting as HCM-like manifestations associ- The most common causes of HCM-related death are sudden ated with WPW syndrome.20–24 Table 5 lists major diseases death, heart failure, and stroke which is usually embolic and presenting as HCM-like hypertrophy and their disease-causing associated with atrial fibrillation.31,32 In a large-scale epide- genes.18,25 Hypertrophic cardiomyopathy-like hypertrophy miological survey conducted in 2002 in Japan, the annual may also develop in patients with Pompe disease, Barth syn- mortality rate among HCM patients was 2.8%.33 The cause of drome, Noonan syndrome, and LEOPARD syndrome. death was arrhythmia in 31.9%, and heart failure in 21.3%. In an analysis of 86 cases of HCM-related death in Western countries,34 the cause of death was sudden death in 44 patients 3. Pathophysiology and Hemodynamics (51%), heart failure-related death in 31 patients (36%), and stroke death in 11 patients (13%). Sudden death was most Hypertrophic cardiomyopathy is characterized by an uneven common in young patients (mean age: 45 years), while heart myocardial hypertrophy associated with diastolic dysfunction failure-related death was more common in midlife and beyond which cannot be explained by pressure overload.26,27 Hyper- (56 years), and stroke developed in older patients (73 years). trophic cardiomyopathy may cause a pressure gradient in re-

II Diagnosis

Figure 1 outlines the diagnostic pathway for HCM. windows and those with low quality of echocardiograms, Abnormal myocardial hypertrophy may be effectively dem- cardiac computed tomography (CT) or cardiac MRI are used.35 onstrated by echocardiography. For patients with limited echo Patients with abnormal electrocardiographic findings such as

Symptoms/Screening

History taking Physical examination ECG Chest X-ray Valvular disease Congenital heart disease Echocardiography/ Hypertensive heart disease Doppler-echocardiography Ischemic heart disease Assessment of cardiac Metabolic disorders contractile/diastolic Systemic disorders; Cardiac radionuclide imaging functions Amyloidosis Cardiac CT, Cardiac MRI Fabry disease, etc. Cardiac catheterization Coronary angiography Endomyocardial biopsy Genetic diagnosis

Definitive diagnosis

Figure 1. Diagnostic charts for HCM. HCM, hypertrophic cardiomyopathy; ECG, electrocardiography; CT, computed tomography; MRI, magnetic resonance imaging.

Circulation Journal Vol.80, March 2016 758 JCS Joint Working Group abnormal Q waves and ST-T changes that are not otherwise Doppler echocardiography should be performed to evaluate 1) explained should be examined in detail with a possibility of the presence/absence of left or right ventricular obstruction HCM in mind.30,36–41 such as LVOT gradient, 2) left ventricular diastolic function, and 3) presence/absence of complications such as mitral regurgitation (MR).26,57–61 When lesions are difficult to be visu- 1. Symptoms and Physical Findings alized with echocardiogram, other imaging techniques such as cardiac CT and cardiac MRI should be used to make a diag- (1) Symptoms nosis based on the comprehensive assessment of the patient. Some patients with HCM are asymptomatic, but others have dyspnea, chest pain, palpitations, and syncope, among other Indications for Transthoracic Echocardiography in symptoms.36 Patients Who Have or Are Suspected to Have HCM: Class I (2) Physical Findings 1. Morphological and hemodynamic evaluation in patients Double apical impulse and fourth heart sound are often pres- suspected to have HCM. ent.29 When LVOT obstruction is present, the physician may 2. Reevaluation of HCM patients with obvious clinical hear an ejection systolic murmur caused by turbulent blood changes or those who need echocardiographic informa- flow through an obstructed site, and, at times, an early sys- tion to determine pharmacotherapy. tolic sound that occurs when the anterior mitral valve leaflet Class II hits against the hypertrophied ventricular septum.42,43 1. Reevaluation of HCM patients without substantial clinical changes. (Excluding annual or semiannual follow-up echocar- 2. Evaluation Method diography.) 2. Evaluation of left ventricular function to stratify prog- 1. Electrocardiography (ECG), Holter ECG, Signal-Averaged nostic risks. ECG, Exercise ECG, Microvolt T-Wave Alternans, and Clinical Electrophysiological Testing Indications for Transesophageal Echocardiography in If 12-lead ECG shows abnormal Q waves, ST-T changes, Patients Who Have or Are Suspected to Have HCM: negative T waves, and/or tall R waves in the left precordial Class I leads which are not otherwise explained, HCM should be 1. Patients with clinical and/or transthoracic echocardio- suspected.30,38–40 Hypertrophic cardiomyopathy is associated graphic features strongly suggestive of HCM in whom with diverse types of arrhythmias such as ventricular or supra- the quality of transthoracic echocardiogram is not suffi- ventricular tachyarrhythmias and bradyarrhythmias,44–47 which cient to evaluate the status of the LVOT gradient and may lead to syncope, sudden death, or cardiogenic thrombo- other hemodynamics. embolism.48–51 Since these arrhythmias are often asymptom- 2. Patients in whom chordal rupture is suspected as the atic, all patients suspected to have HCM should undergo cause of severe MR or acute deterioration of hemody- Holter ECG. namics and who need detailed examination of the mitral The validity of ventricular late potentials detected with apparatus.62 signal-averaged ECG as a predictor of sudden death or lethal 3. Intraoperative monitoring during septal myotomy/myec- arrhythmias has not been demonstrated.52,53 tomy.63 Electrophysiological testing is indicated for the follow- 4. Patients with atrial fibrillation in whom left atrial throm- ing:54–56 bi are suspected and/or electrical defibrillation is considered. Indications for Electrophysiological Testing in HCM Class II Patients: 1. Reevaluation of HCM patients without substantial clini- Class I cal changes. 1. HCM patients resuscitated from cardiac arrest to deter- Class III mine the cause of cardiac arrest and assess the indication 1. Routine reevaluation of patients with clinically stable for ICDs. HCM in whom no modification of treatment is consid- 2. Patients with symptomatic HCM in whom ventricular ered. late potentials were observed in signal-averaged ECG. Class II 3. Cardiac Catheterization (Including Endomyocardial 1. Patients with nonobstructive HCM to investigate the Biopsy) cause of syncope. Noninvasive cardiac imaging modalities including echocar- 2. HCM patients with nonsustained ventricular tachycardia diography, Doppler echocardiography, cardiac CT, and car- which is multiplet or develops frequently. diac MRI may be used in the assessment of HCM, but cardiac Class III catheterization may also be required to evaluate morphologi- 1. HCM patients without ventricular tachycardia who show cal and functional assessment of the ventricles,27,64–66 and to a significant pressure gradient which may explain syn- perform coronary angiography and endomyocardial biopsy to cope. differentiate HCM from coronary artery disease and other specific cardiomyopathies.67 2. Echocardiogram and Doppler Echocardiogram As the basic pathophysiological features of HCM are abnor- Indications for Cardiac Catheterization for the Diagnosis mal myocardial hypertrophy unassociated with ventricular cav- and Assessment of HCM: ity enlargement, two-dimensional echocardiography should be Class I performed to assess the pattern of cardiac hypertrophy, and 1. Coronary angiography to differentiate HCM from coro-

Circulation Journal Vol.80, March 2016 JCS Guidelines for Diagnosis and Treatment of Patients With HCM 759

Step 1: From symptom to suspicion of HCM

Palpitations Asymptomatic Symptoms Shortness of breath Syncope Thump sensation Chest discomfort Dyspnea Dizziness Irregular pulse Chest pain Fatigue

Due to pulmonary Due to LVOT Due to Due to myocardial congestion/increased obstruction? arrhythmias? ischemia? left atrial pressure?

Detailed history taking Family history, Past history (including screening), Occupational history, Smoking/Drinking∙Drug use

Large a wave of jugular pulse Pulse/Carotid pulse: Physical Points of differential findings Double apical impulse bisferiens pulse Intense fourth sound LVOT ejection murmur diagnosis Systolic murmur Findings suggestive (Crackles indicating alveolar fluid) of contractile dysfunction?

Examination ECG: Findings suggestive findings Left atrial overload Left ventricular hypertrophy of other causes of High R wave voltages Abnormal Q wave cardiac hypertrophy? ST-T changes Giant negative T waves Rhythm disturbance Conduction disturbance

Chest X ray: Normal or mild cardiomegaly Increased venous distribution in the upper lung field

Suspected Cardiac hypertrophy LVOT obstruction Arrhythmia conditions Diastolic dysfunction

Echocardiography

Step 2: Diagnosis of HCM by echocardiography

Echocardiography/Doppler-echocardiography

Normal LV wall motion Points for differential diagnosis during echocardiography

Abnormal valves - Identify the localization of abnormal hypertrophy Cardiac hypertrophy due to valvular disease - Blood flow acceleration in the ventricle - SAM Normal LV wall LV enlargement/Reduced - Mitral regurgitation motion and thickness wall motion

・ LV inflow pattern "Abnormal ECG" Dilated - Patterns of abnormal relaxation - Restrictive cardiomyopathy - Pseudonormalized filling pattern cardiomyopathy (RCM) (DCM) - Restrictive filling pattern - Arrhythmogenic right ・ Early diastolic inflow velocity at the mitral ventricular cardiomyopathy annulus obtained via tissue Doppler imaging (ARVC)

Hypertrophic cardiomyopathy (HCM) Dilated phase of hypertrophic cardiomyopathy (D-HCM)

Step 3: Detailed examination of pathophysiology and severity of HCM (Figure 2 continued the next page.) Assessment of LV morphology Assessment of intraventricular Assessment of LV Assessment for Assessment for Assessment for (location of thickened wall) obstruction diastolic function arrhythmias myocardial ischemia causative factors - Maron’ s classification - Location - Apical HCM - Severity - Condition of the mitral valve Circulation Journal Vol.80, March 2016 Echocardiography/Doppler-echocardiography (transthoracic/transesophageal) Holter ECG Detailed family history taking

Genetic testing Cardiac MRI QT interval and QT dispersion on ECG - Assessment of LP on signal-averaged ECG LV morphology Endocrinological/ - Assessment of Immunological myocardial fibrosis (LGE) testing Exercise testing

Myocardial scintigram

Intracardiac pressure recording, Left ventriculogram EPS Coronary angiography

Myocardial biopsy Cardiac catheterization Step 1: From symptom to suspicion of HCM

Palpitations Asymptomatic Symptoms Shortness of breath Syncope Thump sensation Chest discomfort Dyspnea Dizziness Irregular pulse Chest pain Fatigue

Due to pulmonary Due to LVOT Due to Due to myocardial congestion/increased obstruction? arrhythmias? ischemia? left atrial pressure?

Detailed history taking Family history, Past history (including screening), Occupational history, Smoking/Drinking∙Drug use

Examination ECG: findings Left atrial overload Left ventricular hypertrophy Findings suggestive High R wave voltages Abnormal Q wave of other causes of ST-T changes Giant negative T waves cardiac hypertrophy? Rhythm disturbance Conduction disturbance

Chest X ray: Normal or mild cardiomegaly Increased venous distribution in the upper lung field

Suspected Cardiac hypertrophy LVOT obstruction Arrhythmia conditions Diastolic dysfunction

Echocardiography

Step 2: Diagnosis of HCM by echocardiography

Echocardiography/Doppler-echocardiography

Normal LV wall motion Points for differential diagnosis during echocardiography

760 Hypertrophic cardiomyopathy (HCM) Dilated phaseJCS of hypertrophicJoint Working Group cardiomyopathy (D-HCM)

Step 3: Detailed examination of pathophysiology and severity of HCM

Assessment of LV morphology Assessment of intraventricular Assessment of LV Assessment for Assessment for Assessment for (location of thickened wall) obstruction diastolic function arrhythmias myocardial ischemia causative factors - Maron’ s classification - Location - Apical HCM - Severity - Condition of the mitral valve

Echocardiography/Doppler-echocardiography (transthoracic/transesophageal) Holter ECG Detailed family history taking

Myocardial scintigram

Intracardiac pressure recording, Left ventriculogram EPS Coronary angiography

Myocardial biopsy Cardiac catheterization

Figure 2. Diagnostic flow charts for stepwise diagnosis. LVOT, left ventricular outflow tract; ECG, electrocardiography; EPS, electrophysiological studies; LV, left ventricular; SAM, systolic anterior motion; RV, right ventricular; LP, late potential; LGE, late gadolinium enhancement; MRI, magnetic resonance imaging.

nary artery disease. ventricular hypertrophy and predict the prognosis of 2. Endomyocardial biopsy to differentiate HCM from spe- patients with HCM. cific cardiomyopathies.67 2. Myocardial fatty acid metabolism imaging to assess 3. HCM patients who cannot be assessed with echocar- myocardial damage and predict the prognosis of patients diography and need the following: with HCM. - Morphological and functional assessment of ventricles. 3. Myocardial sympathetic nerve imaging to assess myo- - Assessment of efficacy of dual chamber pacing in the cardial damage and predict the prognosis of patients treatment of HOCM. with HCM. - Morphological and functional assessment of ventricles 4. RI angiography to assess left ventricular morphology before and after surgical treatment of HOCM. and function in patients who can be assessed with echo- - Assessment of drug efficacy. cardiography. Class II 5. Pyrophosphate scintigraphy to rule out cardiac amyloi- 1. Morphological, functional or efficacy assessment of ven- dosis and cardiac sarcoidosis.78,79 tricles where echocardiography, cardiac CT or cardiac 6. Gallium scintigraphy to rule out cardiac sarcoidosis. MRI may be used. 7. Fluorodeoxyglucose positron emission tomography (FDG-PET) to assess myocardial metabolic damage.80,81 4. Cardiac Radionuclide and Other Imaging Techniques (1) Cardiac Radionuclide Imaging Techniques (2) Cardiac CT and Cardiac MRI Cardiac radionuclide imaging techniques can assess myocar- Cardiac CT and cardiac MRI are used in morphological as- dial blood flow,68,69 myocardial metabolism,70,71 and myocar- sessment in patients with suspected HCM when echocardiog- dial sympathetic nerve function,72,73 which cannot be assessed raphy does not provide a definitive answer.35 These techniques with other techniques, and are useful in the prediction of are especially useful in identifying thickening of the apex in prognosis.74,75 patients with apical HCM in whom echocardiography does not provide sufficient information.82,83 Cine mode MRI may also Indications for Cardiac Radionuclide Imaging to Diagnose be used in the assessment of left ventricular function, and or Assess HCM: provides similar information to contrast left ventriculography. Class I Late gadolinium enhancement on contrast-enhanced MRI is 1. Radioactive isotope (RI) angiography to assess left ven- considered to represent myocardial fibrosis in HCM.84,85 In tricular function76,77 in patients who cannot be assessed studies on the relationship between LGE and prognosis of with echocardiography. HCM, LGE was significantly associated with cardiac death, Class II sustained ventricular tachycardia or ventricular fibrillation, 1. Myocardial perfusion imaging to assess abnormal left and appropriate ICD discharge, among other factors. These

Circulation Journal Vol.80, March 2016 JCS Guidelines for Diagnosis and Treatment of Patients With HCM 761

School physical examination Suspected HCM Consultation of general practitioner Syncope/Chest pain Abnormal ECG findings S3/S4

Family history, symptoms, physical findings HCM excluded End ECG, chest X-ray, echocardiography Probably excluded End (To be evaluated whenever necessary)

Definite Possible HCM No findings suggestive HCM of HCM

Exercise testing, Cardiac radionuclide imaging, Holter ECG

Findings suggestive of HCM

Risk factors are present Management/Treatment

Cardiac catheterization Options - Endomyocardial biopsy - Genetic testing

Figure 3. Diagnostic flow charts for HCM during childhood. HCM, hypertrophic cardiomyopathy; ECG, electrocardiography.

findings suggest that LGE may be an independent predictor of will undergo genetic testing by his/her own will, and the pa- adverse outcome.86–89 tient’s rights, privacy and information are protected.94–101

Indications for Cardiac CT and Cardiac MRI in Patients With HCM or Suspected HCM to Assess the Patient’s 3. Diagnostic Flow Charts Condition: Class I The diagnosis of HCM is made via several steps from simple 1. Morphological and functional diagnosis in patients with initial examinations such as history taking and physical ex- suspected HCM when echocardiography is inadequate amination to invasive diagnostic examinations such as cardiac for evaluation. catheterization and endomyocardial biopsy. It is important to 2. Morphological and functional diagnosis in patients with assess the patient for cardiac hypertrophy/diastolic dysfunc- suspected apical HCM.83,90 tion, LVOT obstruction, and various arrhythmias.44,59,65,102 Class II Echocardiography should be used as the main diagnostic tech- 1. Morphological and functional diagnosis in patients with nique as it provides detailed information at the initial stage of HCM other than those with apical hypertrophy.90 diagnosis. There are several diagnostic steps from the point 2. Differentiation from previous myocardial infarction and where HCM is first suspected, and then echocardiography, and specific cardiomyopathies based on LGE.90 finally cardiac catheterization to assess the pathophysiology 3. Risk stratification of patients based on LGE. and severity of HCM in detail. Figure 2 shows diagnostic Class III flow charts in the following steps. 1. Patients in whom respiratory or ECG-gated imaging is not feasible. 1. Step 1: Suspicion of HCM -- At general practice including non-cardiovascular physicians 5. Genetic Diagnosis 2. Step 2: Diagnosis of HCM by echocardiography -- At Genetic diagnosis is difficult and not available in many institu- outpatient cardiac clinic tions, but is effective in the diagnosis of specific types of 3. Step 3: Examination of pathophysiology and severity of HCM.91–93 The advancement of genetic analysis technology HCM--Detailed assessment during hospitalization will make genetic diagnosis more common in the future. Eth- ical considerations are essential aspects in genetic diagnosis. It is important to differentiate HCM from other diseases Physicians must ensure that the patient decides whether he/she associated with HCM-like hypertrophy as some HCM-like

Circulation Journal Vol.80, March 2016 762 JCS Joint Working Group

Table 6. Specific Cardiomyopathies to Be Differentiated From HCM in Children Disease Mechanism/Manifestations Cardiac findings Noonan syndrome Unusual facial characteristics, short stature, Pulmonary valve stenosis due to dysplastic valves, webbed neck and other manifestations similar to HCM-like hypertrophy, especially that associated Turner syndrome. with substantial septal thickening, and atrial septal Affected individuals have normal chromosome defect may be present. studies, but a linkage to 12q24 has been reported. LEOPARD syndrome Characterized by brown macules occurring in a Mild pulmonary artery stenosis, HCM-like (multiple lentigines syndrome) large number over the neck and trunk skin, mild hypertrophy similar to obstructive hypertrophic growth retardation, ocular hyperteleorism, cardiomyopathy, and PQ prolongation may be malformed ears, moderate sensorineural deafness, observed. and abnormal genitalia. Similarity to Noonan syndrome has been reported. Pompe disease Acid α-glucosidase deficiency results in the Substantial myocardial thickening and slight left excessive accumulation of glycogen in the body. ventricular enlargement are present. Typical ECG This disorder observed in infants is referred to as findings with substantially high R wave voltages Pompe disease. Pompe disease typically occur in and a short PQ interval are present. the early infantile. The infants often adapt a frog position because of skeletal muscle weakness. The prognosis is poor and patients die of dyspnea or heart failure. Enzyme supplementation is effective. Danon disease A lysosomal glycogen storage disease due to Patients have specific autophagic vacuoles that are LAMP-2 gene mutation. Glycolytic enzymes are present in their muscle cells. As myopathy is mild, intact. Danon disease is an X-linked dominant patients often present with cardiomyopathy in their disorder and is characterized by myopathy in teens. males, mental retardation, and cardiomyopathy. Fabry disease An X-linked recessive genetic disorder of glycolipid HCM-like hypertrophy is the most common cardiac metabolism due to α-galactosidase deficiency. manifestation. Mitral valve prolapse/mitral Accumulation of globotriaosylceramide and regurgitation and aortic regurgitation may also galabiosylceramide is observed in the vascular develop. Some patients may only have cardiac intima, connective tissues, heart and kidney. The manifestations without systemic findings. This type disease locus was mapped to Xp22 region. of disease, which is designated “cardiac Fabry Symptoms are typically first experienced in early disease,” typically manifests in middle age or later. childhood or later, and include pain in the extremities, angiokeratoma, arthralgia, proteinuria, and corneal opacity. Enzyme supplementation is conducted. Friedreich’s ataxia A progressive familial spinocerebellar ataxia. HCM-like manifestations develop frequently. Infant of diabetic mother (IDM) Maternal hyperglycemia induces fetal 5~30% of IDMs have asymmetric septal hyperinsulinemia, which is associated with hypertrophy (ASH). Ventricular outflow tract increased protein synthesis and cardiac myocyte obstruction may develop and cause hemodynamic hypertrophy. dysfunction. These changes disappear in the first week after birth. von Recklinghausen disease A condition caused by mutations of the NF1 gene, Common manifestations include pulmonary artery which is located at chromosome 17q11.2. Also stenosis and tetralogy of Fallot. HCM-like known as neurofibromatosis 1. Café-au lait spots manifestations have also been reported. and multiple neurofibroma are seen. Twin-to-twin transfusion A complication of monochorionic twin pregnancies, In the recipient, volume overload causes syndrome (TTTS) caused by a net inter-twin transfusion of blood from myocardial thickening, leading to heart failure. one fetus (the donor) towards the other fetus (the Intrauterine death occurs frequently. Even if the recipient) through placental anastomoses. babies are born, they often do not respond to treatment and mortality is very high. Congenital myotonic dystrophy An autosomal dominant disorder characterized by Conduction disturbance and axis deviation may skeletal muscle atrophy, muscular weakness, develop. In a case series reported by Kurosaki et mental retardation, and cataract. This disease is al., 7 of the 11 children who underwent caused by a triplet repeat expansion in the echocardiography had ASH.118 myotonin protein kinase gene at chromosome 19q13.3. Mitochondrial disease A condition caused by mitochondrial gene mutation Ventricular wall thickening is present. that causes morphological and functional abnormalities in skeletal muscles and myocardium. Mitochondrial malformation may be observed under electron microscope. HCM, hypertrophic cardiomyopathy; ECG, electrocardiography. diseases may respond to specific treatment. dren, and may be suspected during school physical examination or other routine health screening. Figure 3 shows a diagnostic flow chart for children, and Table 6 lists specific 4. Diagnosis of Hypertrophic cardiomyopathies that should be differentiated from HCM.103–117 Cardiomyopathy in Children

Hypertrophic cardiomyopathy is often asymptomatic in chil-

Circulation Journal Vol.80, March 2016 JCS Guidelines for Diagnosis and Treatment of Patients With HCM 763

III Treatment

In HCM, sarcomere protein gene mutations are considered to and Doppler echocardiography.133 Preventive antibiotic treat- cause increased contractile force leading to increased energy ment should be considered during childbirth and the puerpe- consumption, which induces myocardial hypertrophy.17–19 Ab- rium in order to prevent infective endocarditis. normally high intracellular calcium concentration levels are also considered to be a cause of cardiac hypertrophy and left 4. Alcohol and Tobacco Consumption ventricular diastolic dysfunction in HCM,19 and research is A small amount of ethanol (50 mL of a beverage containing being conducted to find treatment modalities to normalize in- 40% alcohol) induces a reduction in systolic blood pressure, tracellular calcium concentration. an increase in systolic anterior motion (SAM) of the mitral Figure 4 shows treatment flow charts for HCM. valve, and an increase in LVOT gradient.134 Also, alcohol enhances sympathetic nerve activity and heart rate, drinking should therefore be discouraged in patients with HCM. Smok- 1. Management of Daily Life ing may, at times, trigger coronary spasms in patients with HCM.135 1. Physical Activity Competitive sports should not be allowed in principle.119,120 It 5. Infection Control is reasonable for patients with HCM to participate in some As the risk of infective endocarditis is high in patients with low-intensity sports.121 Extreme care should be taken particu- HCM, preventive oral antibiotic treatment is essential.136,137 larly in high-risk patients (Table 7).119,122 Careful management should be given during and immediately after exer- 6. Prevention of Thromboembolism cise.123 Both elderly and younger patients with HCM may experience cardiogenic thromboembolism.32,34,138 Anticoagulation therapy 2. Sexual Activities with or without antiplatelets is essential for patients with As heart rate and blood pressure increase during sexual inter- HCM associated with atrial fibrillation.139 course,124 patients with HOCM should receive sufficient pharmacotherapy and should be at the stable state before resuming 7. Genetic Counseling sexual activity.125,126 Genetic counseling by a clinical genetic specialist may be needed for the patient and his/her family members.140,141 3. Pregnancy As hemodynamics changes during pregnancy and childbirth, it is important to be aware that pregnancy and childbirth are 2. Pharmacotherapy associated with increased risk in women with HCM.122,127–132 During childbirth, the patient’s hemodynamics can be moni- The purpose of pharmacotherapy in patients with HCM is to tored with non-invasive techniques such as echocardiography 1) improve prognosis, 2) alleviate symptoms, and 3) prevent

Hypertrophic cardiomyopathy

Symptoms (-) Symptoms (+) Arrhythmias (+) High-risk patients with clinical or Arrhythmias (-) genetic risk factors for sudden death Normal cardiac function

Follow-up with no treatment Non-obstructive Obstructive amiodarone ICDs verapamil (?) β-blockers (?) β-blockers, -blockers, β Calcium antagonists, Calcium antagonists disopyramide, cibenzoline + + Atrial fibrillation Atrial fibrillation Ventricular tachycardia For heart failure: ACE inhibitors, Supraventricular Ventricular fibrillation ARBs, diuretics For heart failure: ACE inhibitors, ARBs, diuretics tachycardia WPW syndrome

Continue Heart Surgery, Pacemaker pharmacotherapy transplantation implantation, PTSMA Antiarrhythmic Antiarrhythmic Antiarrhythmic if responded well drugs drugs drugs (e.g., (e.g., disopyramide, Catheter ablation disopyramide, amiodarone) amiodarone)

Anticoagulants ICDs

(Catheter ablation + Pacemaker)

Figure 4. Treatment flow charts for HCM. HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter-defibrillator; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; WPW, Wolff-Parkinson-White; PTSMA, percutaneous transluminal septal myocardial ablation.

Circulation Journal Vol.80, March 2016 764 JCS Joint Working Group

Table 7. Risk Factors for Sudden Death 2) Non-Obstructive HCM β-blockers and verapamil are effective in patients with exer- Major risk factors tional dyspnea and chest pain.144 It is unclear whether mono- - Cardiac arrest (ventricular fibrillation) therapy of β-blockers or verapamil, or combined therapy with - Spontaneous sustained ventricular tachycardia both drugs, is more effective. - Family history of premature sudden death (<40 years) - Unexplained syncope Class I - Extreme left ventricular hypertrophy (left ventricular wall β-blockers thickness ≥30 mm) verapamil, diltiazem - Nonsustained ventricular tachycardia on Holter ECG - Abnormal blood pressure response during upright exercise (3) Patients With Heart Failure Possible risk factors 1) HOCM - Dilated phase of hypertrophic cardiomyopathy Patients with a severe LVOT gradient should be treated with - Left ventricular apical aneurysm β-blockers and sodium channel blockers. Angiotensin-con- - Left ventricular outflow tract obstruction verting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are contraindicated for this patient popula- - Extensive late gadolinium enhancement by MRI tion. Non-pharmacotherapy should be considered for patients - Atrial fibrillation not responding to pharmacotherapy. - High-risk gene mutations Modifiable risk factors Class I - Intense exercise (competitive athletics) Patients with LVOT obstruction: β-blockers, verapamil, and - Coronary artery disease diltiazem ECG, electrocardiography; MRI, magnetic resonance imaging. Patients with diastolic dysfunction: β-blockers, verapamil, and diltiazem Patients with systolic dysfunction: diuretics, ACE inhibitors, and ARBs complications.142–145 Class II Table 8 lists drugs used for pharmacotherapy of HCM. Patients with LVOT obstruction: cibenzoline, and disopyramide (1) Asymptomatic Patients (Excluding Young Patients and Class III: Harm High-Risk Patients) Drugs with negative inotropic effects for patients with se- There is no clear evidence on the efficacy of pharmacotherapy vere systolic dysfunction (small doses of β- blockers may in asymptomatic patients.143,155 be used in tolerable cases). ACE inhibitors and ARBs in patients with a severe LVOT Class I gradient None. Class II 2) Non-Obstructive HCM β-blockers, verapamil Patients with heart failure associated with HCM and those with D-HCM should be treated similarly to those for patients (2) Symptomatic Patients (Mild or Moderate) with heart failure (See the Guidelines for Treatment of Chron- 1) HOCM ic Heart Failure published by the Japanese Circulation Society β-blockers, negative inotropic calcium antagonists (e.g., vera- [JCS 2010]154). pamil and diltiazem), and Class Ia antiarrhythmic drugs (e.g. Patients with systolic dysfunction should be treated with disopyramide and cibenzoline) are used.122,144,145,156,157 As cal- diuretics, ACE inhibitors and ARBs. cium antagonists may increase the LVOT gradient by dilating peripheral blood vessels, these drugs should be used with Class I caution.144,158 Patients with diastolic dysfunction: β-blockers, verapamil and diltiazem Class I Patients with systolic dysfunction: ACE inhibitors, ARBs β-blockers and diuretics verapamil, diltiazem Class II Class II (Note 1) None. disopyramide Class III: Harm cibenzoline Drugs with negative inotropic effects for patients with se- Class III: Harm vere systolic dysfunction (small doses of β-blockers may be The use of dihydropyridine calcium antagonists and drugs used in tolerable cases). with positive inotropic effect in patients with severe LVOT obstruction. (4) High-Risk Group Note 1: The use of disopyramide and cibenzoline is listed as In order to prevent sudden death, high-risk patients should be Class II recommendations as these drugs have not treated aggressively regardless of the presence or absence of been evaluated in large-scale clinical studies, but symptoms. Patients with nonsustained or sustained ventricular there is general agreement that these drugs are effec- tachycardia are indicated for amiodarone and ICDs.44,159–162 tive in reducing the LVOT gradient.

Circulation Journal Vol.80, March 2016 JCS Guidelines for Diagnosis and Treatment of Patients With HCM 765

Table 8. List of Drugs for the Treatment of HCM ISA Overseas reports Daily dose approved in Japan β-blockersa propranolol Class I Group 2 – 120~160 mg/day 60~120 mg/day bufetolol 15 mg/day bupranolol 50 mg/day 30~60 mg/day bucumolol 15~30 mg/day befunolol 30~90 mg/day nadolol Group 4 – 40~80 mg/day 30~60 mg/day timolol 20 mg/day 10~20 mg/day tilisolol 10~20 mg/day metoprolol Class II Group 4 – 150~300 mg/day 60~120 mg/day atenolol 50~100 mg/day 50~100 mg/day bisoprolol 5~10 mg/day 5 mg/day betaxolol 5~80 mg/day 2.5~20 mg/day Calcium antagonistsb verapamil 240 mg/day 120~240 mg/day 360~480 mg/day diltiazem None 90~180 mg/day nifedipine* 10 mg (sublingually) 10~20 mg (sublingually) Antiarrhythmic drugsc disopyramide 600~800 mg/day 300 mg/day (*) cibenzoline 260~390 mg/day 300 mg/day (*) ACE inhibitorsd enalapril SOLVD 5~10 mg/day Initial dose: 5 mg/day Start at 2.5 mg/day Target dose: 20 mg/day Actual dose: Prevention trial146 16.7 mg/day Treatment trial147 16.6 mg/day CONSENSUS148 Initial dose: 10 mg/day Target dose: 20 mg/day, Maximum dose: 40 mg/day Actual dose: 18.4 mg/day lisinopril ATLAS149 5~10 mg/day Initial dose: 2.5~5 mg/day Start at 2.5 mg/day in patients with renal Target dose: disorder and elderly patients Low dose: 2.5~5 mg/day High dose: 32.5~35 mg/day Angiotensin receptor blockerse losartan ELITE II150 25~100 mg/day Initial dose: 12.5 mg/day Target dose: 50 mg/day Actual dose: 42.6 mg/day candesartan CHARM151 Start at 4 mg/day (2 mg/day for severe Initial dose: 4 or 8 mg/day patients) Target dose: 32 mg/day Maintenance dose: 8 mg/day Actual dose: 24 mg/day Hypertensive patients: 4~8 mg/day ARCH-J152 (maximum dose: 12 mg/day) Initial dose: 4 mg/day Start at 2 mg/day in patients with renal Target dose: 8 mg/day disorder Actual dose: 8 mg/day valsartan Val-HeFT153 40~80 mg/day (maximum dose: Target dose: 320 mg/day 160 mg/day) Actual dose: 254 mg/day Covered with the National Health Insurance; a: hypertension, angina pectoris, and tachyarrhythmia. b: verapamil -- ischemic heart diseases such as myocardial infarction and angina pectoris; diltiazem -- hypertension, angina pectoris. c: disopyramide -- tachyarrhythmia; cibenzoline -- tachyarrhythmia (cibenzoline has not been launched in the United States). d: hypertension and heart failure. e: hypertension. (*) Dose for patients with premature contraction and paroxysmal tachycardia. *Should not administered sublingually as acute hypotension and reflective tachycardia may develop. Data on enalapril, lisinopril, losartan, candesartan, and valsartan were referred from the Guidelines for Treatment of Chronic Heart Failure (JCS 2010).154 HCM, hypertrophic cardiomyopathy; ISA, intrinsic sympathomimetic activity; ACE, angiotensin converting enzyme; SOLVD, Studies of Left Ventricular Dysfunction; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; ATLAS, Assessment of Treatment with Lisinopril and Survival; ELITE II, Evaluation of Losartan in the Elderly Study II; CHARM, Candesartan in Heart failure Assess- ment of Reduction in Mortality and morbidity; ARCH-J, Assessment of Response to Candesartan in Heart failure in Japan; Val-HeFT, Valsar- tan Heart Failure Trial.

Circulation Journal Vol.80, March 2016 766 JCS Joint Working Group

Positioning of Treatments for the Prevention of Sudden Class III: Harm Death in Patients With HCM: 1. Asymptomatic patients with pharmacologically control- Class I lable HOCM. 1. ICD therapy for patients with HCM successfully resus- 2. Symptomatic patients with HCM without provocable citated from cardiac arrest. LVOT gradient. Class II 1. ICD therapy or amiodarone for the primary prevention 2. Device Therapy of sudden death. (1) Dual-Chamber (DDD) Pacing for the Treatment of LVOT Gradient168–173 (5) Arrhythmias Class I Class I 1. Patients who have a significant LVOT gradient causing β-blockers, verapamil, diltiazem, Class Ia and Ic antiar- symptoms that impair the patient’s QOL, and require rhythmic drugs and amiodarone. permanent pacemakers for reasons other than HOCM Warfarin therapy for patients with atrial fibrillation. (such as drug-induced bradycardia).(Note 1) (*) Catheter ablation may be indicated for patients with drug- Class II resistant atrial fibrillation with a rapid ventricular response, 1. HOCM patients with symptoms that correlate with a type I atrial flutter, paroxysmal supraventricular tachycardia, significant pressure gradient and impair the patient’s or sustained ventricular tachycardia who have experienced QOL who have no other appropriate treatment options syncope and significantly impaired quality of life (QOL). (See due to lack of efficacy or intolerance to drugs.171,173 the Guidelines for Non-Pharmacotherapy of Cardiac Arrhyth- Class III: Harm mias [JCS 2011]163 published by the Japanese Circulation 1. Patients who have no pressure gradient or bradycardia Society.) indicated for pacemaker implantation.(Note 1) Note 1: Based on the Guidelines for Non-Pharmacotherapy of Indications for Pharmacotherapy of Arrhythmias Cardiac Arrhythmias (JCS 2011)163 published by the Associated With HCM: Japanese Circulation Society. Class I 1. Patients with hemodynamically unstable atrial fibrilla- (2) Implantable Cardioverter-Defibrillators (ICDs)162 tion or atrial flutter with a rapid heart rate. Class I 2. Patients with paroxysmal supraventricular tachycardia. 1. Patients with a prior history of sustained ventricular 3. Patients with symptomatic nonsustained ventricular tachycardia, ventricular fibrillation, or cardiac arrest. tachycardia who have risk factors for sudden death. Class IIa 4. Patients with sustained ventricular tachycardia. 1. Patients with nonsustained ventricular tachycardia; a Class II family history of sudden death; syncope; a left ventricu- 1. Patients with symptomatic supraventricular or ventricular wall thickness of ≥30 mm; or abnormal blood pres- lar premature contractions. sure response during exercise. 2. Patients with asymptomatic or hemodynamically stable nonsustained ventricular tachycardia. (3) Cardiac Resynchronization Therapy (CRT)174,175 Class III: Harm Class I 1. Patients with asymptomatic supraventricular or ventricu- 1. Patients with NYHA functional class III or ambulatory lar premature contractions. class IV heart failure despite optimal pharmacotherapy, 2. Patients with asymptomatic bradycardia. a left ventricular ejection fraction (LVEF) of ≤35%, a QRS interval of ≥120 msec, and sinus rhythm. Class IIa 3. Non-Pharmacotherapy 1. Patients with NYHA functional class III or ambulatory class IV heart failure despite optimal pharmacotherapy, 1. Surgery (Septal Myotomy/Myectomy, Mitral Valve a LVEF of ≤35%, a QRS interval of ≥120 msec, and Surgery) atrial fibrillation. Surgery is the oldest known non-pharmacotherapy for HCM, 2. Patients with NYHA functional class III or ambulatory and consistent results have been established.164–166 In Japan, class IV heart failure despite optimal pharmacotherapy, only a small number of institutions have experience of a large and a LVEF of ≤35% who have had or are planned to number of surgical cases of HCM.167 have a permanent pacemaker implanted, and require or are expected to require ventricular pacing frequently. Indications for Surgical Treatment of HCM: Class IIb Class I 1. Patients with NYHA functional class II heart failure, a 1. Patients with drug-resistant HOCM who have New York LVEF of ≤35% who are planned to have permanent Heart Association (NYHA) functional class III or IV pacemaker implanted and are expected to require ven- symptoms, and have a resting LVOT gradient of tricular pacing frequently. ≥50 mmHg. Class III: Harm 2. Patients with drug-resistant HOCM who recovered from 1. Asymptomatic patients with low LVEF who are not in- syncope, and have a resting or provocable LVOT gradi- dicated for pacemaker therapy. ent of ≥50 mmHg. 2. Patients with limited physical activity due to chronic Class II diseases other than heart failure or those suspected with 1. Patients with drug-resistant HOCM who have no or only a life expectancy of 12 months or less. mild symptoms with a resting LVOT gradient of ≥50 mmHg.

Circulation Journal Vol.80, March 2016 JCS Guidelines for Diagnosis and Treatment of Patients With HCM 767 Competition Intense exercise (E - allowed) Name of institution: physician: (seal) of Name Exercise with maximum endurance, speed, and muscle strength Performance, competition, combination of actions Long-distance running, sprint race, competition, time race Competition, swimming marathon, time race, start and turn Time race, applied practice, simplified game, competition Applied practice, competition Dance recitals, etc. Climbing, swimming marathon, diving, canoeing, boating, surfing, wind etc. Playing instruments requiring physical exertion (such as trumpet, trombone, oboe, bassoon, horn), playing or conducting quick rhythmical music, playing in a march - ing band 4. Next visit years months later or when symptoms develop 187 Prohibited 11. · – Simple games using basic movements (adjust according to the time, space and apparatus available to practice collaborative playing, and offensive/defen - sive components) Practicing at golf range Moderate exercise (D, E - allowed) 3. School sport club activity ( ) club of Name (Note: ) Allowed Exercise to improve flexibility, techniques, high-force movement, and endurance Practice of low-grade technique, running start to perform holding, jumping and basic techniques (including rotation) Jogging, short run and jump Slow swimming Training with foot - work (with no close body contact) Practicing simple techniques and forms with modest basic movements Dance with modest basic movements, etc. Walking with ski plates or skates, slow skiing/skating, hiking on flatlands, playing in the water, etc. Most cultural activities not described in the right column 2. Level of management Management needed: A, B, C, D, E needed management No Basic movements (e.g., passing, shooting, dribbling, feinting, lifting, trapping, throwing, kicking, and handling) Basic movements (e.g., passing, servicing, receiving, tossing, feinting, stroking, and shots) Basic movements (e.g., pitching, catching, and batting) Basic movements (light swinging) Mild exercise (C, D, E - allowed) Follow the above intensity of exercise during athletic festival, meetings, ball sports competitions, and exer cise tests. Students other than those in Category “E” should consult with their school physician or attending physicians determini ng whether they will participate special activities such as class trips, training camp, school trip, camp schools, and seaside schools. [Level of management: A - Requires treatment at home or in hospital, B Goes to school but must avoid exercise, C Can do m ild exercise, D - Can do moderate E intense exercise] Light exercise or rhythmic movement to communicate with other students Basic movements (throwing, hitting, catching, kicking, jumping) Calisthenics, light mat exercise, balance jumping Basic motion, standing broad jump, light throwing, jumping (must avoid running) Easy movement in water, float, prone kick and etc. Slow exercise without running Cultural activities not requiring long-term physical activity · · Etiquette, basic movement (e.g., ukemi, swinging, sabaki) Basic movement (e.g., hand gesture, steps, expressions) Playing on water, snow, or ice School Activity Management Table (for Junior and Senior High Students) ( years) School Grade Class Date Intensity of exercise Basketball Handball Soccer Rugby Volleyball Table tennis Tennis Badminton Softball Baseball Cultural activities Warming-up exercise Strength-training exercise (Mat, vaulting horse, horizontal bar, and balance beam) (racing, jumping, throwing) (freestyle, breaststroke, backstroke, butterfly) Goal games Net games Baseball-type games Golf Judo, kendo, sumo Original dance, folk modern dance Play in the snow or on ice, skiing, skating, camping, climbing, swimming, marathon, water- front activities School events and other activities School Activity Management Table Published by the Japanese Society of Health Basic exercise* Apparatus gymnastics Athletics Swimming Ball sports Mild exercise: Physical activities that do not increase respiratory rate in average students at the same age. Moderate exercise: Physical activities that increase respiratory rate without causing shortness of breath in average students a t the same age. Players may talk with partners, if any, during exercise. Intense exercise: Physical activities that increase respiratory rate and cause shortness of breath in average students at the same age. Martial arts Dance Outdoor activity of Sport activity Type sport Table 9. [Revised in 2011] date F Birth / Name M 1. Diagnosis (findings) Remarks Definitions * Basic exercise: including resistance (isometric) exercise. Adapted from The Japanese Society of School Health. Guide for the use Activity Management Table Children with Heart Disease, 2011 revision. 2013: 3

Circulation Journal Vol.80, March 2016 768 JCS Joint Working Group

Hypertrophic cardiomyopathy

Asymptomatic Heart failure Symptomatic Arrhythmias No arrhythmia - Chest pain - Atrial arrhythmias Normal cardiac function - Syncope - Ventricular arrhythmias Abnormal genes Significant obstruction

Limit sports activities Limit sports activities Limit sports activities Limit sports activities (Rank D) (Rank B or C) (Rank B or C) (Rank B or C) No pharmacotherapy? Treatment of heart failure β-blockers Antiarrhythmic drugs β-blockers? β-blockers? Calcium antagonists? (disopyramide, amiodarone) disopyramide? Antithrombotic therapy

Figure 5. Management of children with HCM. HCM, hypertrophic cardiomyopathy.

Table 10. Treatment for Children With HCM: RAPID ACCESS GUIDE Manifestation Class I Class II Class III Asymptomatic Pharmacotherapy is unnecessary in Digoxin and positive inotropic general, but β-blockers and calcium agents are contraindicated. antagonists may be used when Intense sports activities* should necessary. be prohibited. Diastolic dysfunction β-blockers, Calcium antagonists Digoxin and positive inotropic agents are contraindicated. Intense sports activities* should be prohibited. Symptomatic HOCM β-blockers, Calcium antagonists disopyramide, Septal Digoxin and positive inotropic myotomy/myectomy agents are contraindicated. Intense sports activities* should be prohibited. High risk group for sudden β-blockers, Calcium antagonists ICD Digoxin and positive inotropic death** agents are contraindicated. Intense sports activities* should be prohibited. Infants and young children digoxin, Diuretics, Vasodilators β-blockers, ACE inhibitors Intense sports activities* should (often associated with heart be prohibited. failure) Dilated phase of HCM digoxin, Diuretics, Vasodilators β-blockers, ACE inhibitors, Heart Intense sports activities* should transplantation be prohibited. Arrhythmias associated with amiodarone, β-blockers, Septal myotomy/myectomy Digoxin and positive inotropic HCM Calcium antagonists agents are contraindicated. Intense sports activities* should be prohibited. *The School Activity Management Table for Junior and Senior High School Students published by the Japanese Society of School Health should be followed (See Table 9). **Children with a history of cardiac arrest or sustained ventricular tachycardia, a family history of premature sudden death due to HCM, or a history of syncope during physical exertion. HCM, hypertrophic cardiomyopathy; HOCM, hypertrophic obstructive cardiomyopathy; ICD, implantable cardioverter-defibrillator; ACE, angiotensin-converting enzyme.

3. Percutaneous Transluminal Septal Myocardial Ablation Indications for PTSMA for the Treatment of HCM:176–185 (PTSMA) Class I Recently, PTSMA has been increasingly performed in clinical None. practice, and is being established as a treatment option for Class IIa(Note 1) patients with HOCM. However, the long-term outcome of 1. Patients with HOCM who have NYHA functional class PTSMA is unclear at this time, and further accumulation of III or IV symptoms, do not respond to pharmacotherapy, evidence is awaited. and have a resting or provocable LVOT gradient of Since April 2005, PTSMA is covered by the National ≥30 mmHg.178,179,186 Health Insurance. 2. Patients with HOCM who have experienced syncope

Circulation Journal Vol.80, March 2016 JCS Guidelines for Diagnosis and Treatment of Patients With HCM 769

due to LVOT gradient, and have a resting or provocable or intense physical activities (Figure 5).119,121 LVOT gradient of ≥30 mmHg. 3. Patients with drug-resistant atrial fibrillation associated 2. Indications for Pharmacotherapy with a significant LVOT gradient ≥( 30 mmHg). (See Table 10, RAPID ACCESS GUIDE) Class III: Harm 1. Asymptomatic patients with medically controllable 3. Non-Pharmacotherapy HOCM. (1) Surgery 2. Symptomatic HCM patients without LVOT gradient. Septal myotomy/myectomy (Morrow procedure) have rarely Note 1: The use of PTSMA is not a Class I recommendation been used in children, and the long-term outcome of these at present because of the lack of sufficient evidence. procedures is unclear.188–190

(2) Pacemaker Implantation 4. Management and Treatment of Hypertrophic As data on the indications and efficacy of pacemaker implan- Cardiomyopathy in Children tation are limited in children, the use of pacemakers should be considered with caution. 1. Prevention and Management of Sudden Death In the School Activity Management Table 2011 edition pub- (3) PTSMA lished by the Japanese Society of School Health (Table 9),187 As PTSMA may induce myocardial scarring and thereby in- high-risk children are prohibited from almost all types of crease the risk of lethal arrhythmias and sudden death, this sports and competitive athletics, and symptomatic children technique is not recommended for children. with HCM or those with HOCM are prohibited from moderate

References Ltd., 2005 (in Japanese). 14. Kubo T, Kitaoka H, Okawa M, Matsumura Y, Hitomi N, Yamasaki 1. Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, N, et al. Lifelong left ventricular remodeling of hypertrophic car- O’Connell J, et al. Report of the 1995 World Health Organization/ diomyopathy caused by a founder frameshift deletion mutation in International Society and Federation of Cardiology Task Force on the cardiac Myosin-binding protein C gene among Japanese. J Am the Definition and Classification of cardiomyopathies. Circulation Coll Cardiol 2005; 46: 1737 – 1743. 1996; 93: 841 – 842. 15. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F, 2. Brigden W. Uncommon myocardial diseases; the non-coronary Lesser JR, et al. Prevalence, clinical profile, and significance of left cardiomyopathies. Lancet 1957; 273: 1179 – 1184. ventricular remodeling in the end-stage phase of hypertrophic car- 3. Goodwin JF, Gordon H, Hollman A, Bishop MB. Clinical aspects diomyopathy. Circulation 2006; 114: 216 – 225. of cardiomyopathy. Br Med J 1961; 1: 69 – 79. 16. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, 4. Takatsu T. Idiopathic cardiomyopathy. The Journal of the Japanese McKenna W, Seidman CE, et al. A molecular basis for familial Society of Internal Medicine 1977; 60: 1669 – 1687 (in Japanese). hypertrophic cardiomyopathy: A beta cardiac myosin heavy chain 5. Brock R. Functional obstruction of the left ventricle; acquired gene missense mutation. Cell 1990; 62: 999 – 1006. aortic subvalvar stenosis. Guy’s Hosp Rep 1957; 106: 221 – 238. 17. Kimura A. Molecular basis of hereditary cardiomyopathy: Abnor- 6. Teare D. Asymmetric hypertrophy of the heart in young adults. Br malities in calcium sensitivity, stretch response, stress response and Heart J 1958; 20: 1 – 8. beyond. J Hum Genet 2010; 55: 81 – 90. 7. Braunwald E, Morrow AG, Cornell WP, Aygen MA, Hilbish TF. 18. Landstrom AP, Ackerman MJ. Mutation type is not clinically useful Idiopathic hypertrophic subaortic stenosis: Clinical, hemodynamic in predicting prognosis in hypertrophic cardiomyopathy. Circula- and angiographic manifestations. Am J Med 1960; 29: 924 – 945. tion 2010; 122: 2441 – 2449; discussion 2450. 8. Report of the WHO/ISFC task force on the definition and classifica- 19. Watkins H, Ashrafian H, Redwood C. Inherited cardiomyopathies. tion of cardiomyopathies. Br Heart J 1980; 44: 672 – 673. N Engl J Med 2011; 364: 1643 – 1656. 9. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, 20. MacRae CA, Ghaisas N, Kass S, Donnelly S, Basson CT, Watkins Arnett D, et al. Contemporary definitions and classification of the HC, et al. Familial Hypertrophic cardiomyopathy with Wolff- cardiomyopathies: An American Heart Association Scientific State- Parkinson-White syndrome maps to a locus on chromosome 7q3. J ment from the Council on Clinical Cardiology, Heart Failure and Clin Invest 1995; 96: 1216 – 1220. Transplantation Committee; Quality of Care and Outcomes Re- 21. Gollob MH, Green MS, Tang AS, Gollob T, Karibe A, Ali Hassan search and Functional Genomics and Translational Biology Inter- AS, et al. Identification of a gene responsible for familial Wolff- disciplinary Working Groups; and Council on Epidemiology and Parkinson-White syndrome. N Engl J Med 2001; 344: 1823 – 1831. Prevention. Circulation 2006; 113: 1807 – 1816. 22. Arad M, Benson DW, Perez-Atayde AR, McKenna WJ, Sparks EA, 10. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron Kanter RJ, et al. Constitutively active AMP kinase mutations cause P, et al. Classification of the cardiomyopathies: A position state- glycogen storage disease mimicking hypertrophic cardiomyopathy. ment from the European Society of Cardiology Working Group on J Clin Invest 2002; 109: 357 – 362. Myocardial and Pericardial Diseases. Eur Heart J 2008; 29: 23. Murphy RT, Mogensen J, McGarry K, Bahl A, Evans A, Osman E, 270 – 276. et al. Adenosine monophosphate-activated protein kinase disease 11. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White et al. 2011 ACCF/AHA guideline for the diagnosis and treatment syndrome: Natural history. J Am Coll Cardiol 2005; 45: 922 – 930. of hypertrophic cardiomyopathy: A report of the American College 24. Arad M, Maron BJ, Gorham JM, Johnson WH Jr, Saul JP, Perez- of Cardiology Foundation/American Heart Association Task Force Atayde AR, et al. Glycogen storage diseases presenting as hyper- on Practice Guidelines. Circulation 2011; 124: e783 – e831, doi: trophic cardiomyopathy. N Engl J Med 2005; 352: 362 – 372. 10.1161/CIR.0b013e318223e2bd. 25. Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and 12. Specified Disease Research Group on Idiopathic Cardiomyopathy therapeutic implications of genetic testing for hypertrophic cardio- of the Japanese Ministry of Health and Welfare. Diagnostic guide- myopathy. J Am Coll Cardiol 2009; 54: 201 – 211. lines for idiopathic cardiomyopathy, annual report for 1985 of the 26. Maron BJ, Spirito P, Green KJ, Wesley YE, Bonow RO, Arce J. Specified Disease Research Group on idiopathic cardiomyopathy Noninvasive assessment of left ventricular diastolic function by of the Japanese Ministry of Health and Welfare. 1986: 13 – 15 (in pulsed Doppler echocardiography in patients with hypertrophic Japanese). cardiomyopathy. J Am Coll Cardiol 1987; 10: 733 – 742. 13. Kitabatake A, Tomoike H, editors. Cardiomyopathy: Diagnostic 27. Hirota Y. A clinical study of left ventricular relaxation. Circulation guidelines and commentary. Research Group on Idiopathic Cardio- 1980; 62: 756 – 763. myopathy, Intractable Disease Research Project of the Japanese 28. Louie EK, Edwards LC 3rd. Hypertrophic cardiomyopathy. Prog Ministry of Health, Labor and Welfare. Sapporo: Karinsha Co., Cardiovasc Dis 1994; 36: 275 – 308.

Circulation Journal Vol.80, March 2016 770 JCS Joint Working Group

29. Fighali S, Krajcer Z, Edelman S, Leachman RD. Progression of 50. Robinson K, Frenneaux MP, Stockins B, Karatasakis G, Poloniecki hypertrophic cardiomyopathy into a hypokinetic left ventricle: JD, McKenna WJ. Atrial fibrillation in hypertrophic cardiomyopa- Higher incidence in patients with midventricular obstruction. J Am thy: A longitudinal study. J Am Coll Cardiol 1990; 15: 1279 – 1285. Coll Cardiol 1987; 9: 288 – 294. 51. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. 30. Kawai C, Wakabayashi A, Hirose K, Sakurai K. The diagnostic Impact of atrial fibrillation on the clinical course of hypertrophic criteria for idiopathic cardiomyopathy. Annual report for 1975 of cardiomyopathy. Circulation 2001; 104: 2517 – 2524. the Specified Disease Research Group on Idiopathic Cardiomyopa- 52. Fauchier JP, Cosnay P, Moquet B, Balleh H, Rouesnel P. Late thy of the Japanese Ministry of Health and Welfare. 1976: 88 – 99 ventricular potentials and spontaneous and induced ventricular ar- (in Japanese). rhythmias in dilated or hypertrophic cardiomyopathies: A prospec- 31. Kawai C, Sakurai K, Kishimoto T, Tomoika N. Prognostic study of tive study about 83 patients. Pacing Clin Electrophysiol 1988; 11: idiopathic cardiomyopathy. Annual report for 1982 of the Specified 1974 – 1983. Disease Research Group on Cardiomyopathy of the Japanese Min- 53. Kulakowski P, Counihan PJ, Camm AJ, McKenna WJ. The value istry of Health and Welfare. 1983: 63 – 66 (in Japanese). of time and frequency domain, and spectral temporal mapping 32. Kubo T, Kitaoka H, Okawa M, Nishinaga M, Doi YL. Hypertrophic analysis of the signal-averaged electrocardiogram in identification cardiomyopathy in the elderly. Geriatr Gerontol Int 2010; 10: of patients with hypertrophic cardiomyopathy at increased risk of 9 – 16. sudden death. Eur Heart J 1993; 14: 941 – 950. 33. Matsumori A, Furukawa Y, Hasegawa K, Sato Y, Nakagawa H, 54. Fananapazir L, Tracy CM, Leon MB, Winkler JB, Cannon RO 3rd, Morikawa Y, et al. Epidemiologic and clinical characteristics of Bonow RO, et al. Electrophysiologic abnormalities in patients with cardiomyopathies in Japan: Results from nationwide surveys. hypertrophic cardiomyopathy: A consecutive analysis in 155 pa- Circ J 2002; 66: 323 – 336. tients. Circulation 1989; 80: 1259 – 1268. 34. Maron BJ, Olivotto I, Spirito P, Casey SA, Bellone P, Gohman TE, 55. Fananapazir L, Chang AC, Epstein SE, McAreavey D. Prognostic et al. Epidemiology of hypertrophic cardiomyopathy-related death: determinants in hypertrophic cardiomyopathy: Prospective evalua- Revisited in a large non-referral-based patient population. Circula- tion of a therapeutic strategy based on clinical, Holter, hemody- tion 2000; 102: 858 – 864. namic, and electrophysiological findings. Circulation 1992; 86: 35. Masuda Y, Watanabe S. CT, MRI. In: Matsuzaki M, editor. Car- 730 – 740. diac practice 11: Introduction to cardiomyopathy. Tokyo: Bunkodo 56. Watson RM, Schwartz JL, Maron BJ, Tucker E, Rosing DR, Co., Ltd., 1996: 52 – 57 (in Japanese). Josephson ME. Inducible polymorphic ventricular tachycardia and 36. McKenna W, Deanfield J, Faruqui A, England D, Oakley C, ventricular fibrillation in a subgroup of patients with hypertrophic Goodwin J. Prognosis in hypertrophic cardiomyopathy: Role of age cardiomyopathy at high risk for sudden death. J Am Coll Cardiol and clinical, electrocardiographic and hemodynamic features. Am J 1987; 10: 761 – 774. Cardiol 1981; 47: 532 – 538. 57. Henry WL, Clark CE, Epstein SE. Asymmetric septal hypertrophy: 37. Ryan MP, Cleland JG, French JA, Joshi J, Choudhury L, Echocardiographic identification of the pathognomonic anatomic Chojnowska L, et al. The standard electrocardiogram as a screening abnormality of IHSS. Circulation 1973; 47: 225 – 233. test for hypertrophic cardiomyopathy. Am J Cardiol 1995; 76: 58. Shapiro LM, McKenna WJ. Distribution of left ventricular hyper- 689 – 694. trophy in hypertrophic cardiomyopathy: A twodimensional echo- 38. Chen CH, Nobuyoshi M, Kawai C. ECG pattern of left ventricular cardiographic study. J Am Coll Cardiol 1983; 2: 437 – 444. hypertrophy in nonobstructive hypertrophic cardiomyopathy: The 59. Maron BJ, Gottdiener JS, Epstein SE. Patterns and significance of significance of the mid-precordial changes. Am Heart J 1979; 97: distribution of left ventricular hypertrophy in hypertrophic cardio- 687 – 695. myopathy: A wide angle, two dimensional echocardiographic study 39. Toshima H, Koga Y, Yamaga A, Hiyamuta K. Pathogenesis of of 125 patients. Am J Cardiol 1981; 48: 418 – 428. abnormal Q waves in patients with hypertensive cardiomyopathy. 60. Stewart WJ, Schiavone WA, Salcedo EE, Lever HM, Cosgrove Heart 1996; 28: 234 – 243 (in Japanese). DM, Gill CC. Intraoperative Doppler echocardiography in hyper- 40. Yamaguchi H, Ishimura T, Nishiyama S, Nagasaki F, Nakanishi S, trophic cardiomyopathy: Correlations with the obstructive pressure Takatsu F, et al. Hypertrophic nonobstructive cardiomyopathy with gradient. J Am Coll Cardiol 1987; 10: 327 – 335. giant negative T waves (apical hypertrophy): Ventriculographic and 61. Nishimura RA, Appleton CP, Redfield MM, Ilstrup DM, Holmes echocardiographic features in 30 patients. Am J Cardiol 1979; 44: DR Jr, Tajik AJ. Noninvasive Doppler echocardiographic evalua- 401 – 412. tion of left ventricular filling pressure in patients with cardiomy- 41. Suzuki J, Sugimoto T, Sakamoto T, Nishikawa J. Apical hypertro- opathies: A simultaneous Doppler echocardiographic and cardiac phy as an etiology of giant negative T waves: Detection of localized catheterization study. J Am Coll Cardiol 1996; 28: 1226 – 1233. hypertrophy at the apical level by magnetic resonance imaging. 62. Zhu WX, Oh JK, Kopecky SL, Schaff HV, Tajik AJ. Mitral regur- Heart 1989; 21: 358 – 362 (in Japanese). gitation due to ruptured chordae tendineae in patients with hyper- 42. Wynne J, Braunwald E. The cardiomyopathies. In: Douglas P, trophic obstructive cardiomyopathy. J Am Coll Cardiol 1992; 20: Zipes DP, Libby P, Bonow RO, Braunwald E. Braunwald’s heart 242 – 247. disease: A text book of cardiovascular medicine, 7th edn. Elsevier 63. Grigg LE, Wigle ED, Williams WG, Daniel LB, Rakowski H. Saunders, 2005; 1673. Transesophageal Doppler echocardiography in obstructive hyper- 43. Sze KC, Shah PM. Pseudoejection sound in hypertrophic subaortic trophic cardiomyopathy: Clarification of pathophysiology and im- stenosis: An echocardiographic correlative study. Circulation 1976; portance in intraoperative decision making. J Am Coll Cardiol 54: 504 – 509. 1992; 20: 42 – 52. 44. McKenna WJ, England D, Doi YL, Deanfield JE, Oakley C, 64. Brockenbrough EC, Braunwald E, Morrow AG. A hemodynamic Goodwin JF. Arrhythmia in hypertrophic cardiomyopathy. I: Influ- technic for the detection of hypertrophic subaortic stenosis. Circu- ence on prognosis. Br Heart J 1981; 46: 168 – 172. lation 1961; 23: 189 – 194. 45. Maron BJ, Savage DD, Wolfson JK, Epstein SE. Prognostic sig- 65. Braunwald E, Lambrew CT, Rockoff SD, Ross J Jr, Morrow AG. nificance of 24 hour ambulatory electrocardiographic monitoring in Idiopathic hypertrophic subaortic stenosis: I. A description of the patients with hypertrophic cardiomyopathy: A prospective study. disease based upon an analysis of 64 patients. Circulation 1964; 30 Am J Cardiol 1981; 48: 252 – 257. (Suppl IV): 3 – 119. 46. McKenna WJ, Oakley CM, Krikler DM, Goodwin JF. Improved 66. Yamaguchi H, Ishimura T. Left ventriculography, coronary angi- survival with amiodarone in patients with hypertrophic cardiomy- ography. Comprehensive textbook on idiopathic cardiomyopathy. opathy and ventricular tachycardia. Br Heart J 1985; 53: 412 – 416. In: Kawai, C, editor. Tokyo: Nankodo Co., Ltd., 1987: 298 – 321 (in 47. Alfonso F, Frenneaux MP, McKenna WJ. Clinical sustained uni- Japanese). form ventricular tachycardia in hypertrophic cardiomyopathy: As- 67. Mason JW, O’Connell JB. Clinical merit of endoyoardial biopsy. sociation with left ventricular apical aneurysm. Br Heart J 1989; Circulation 1989; 79: 971 – 979. 61: 178 – 181. 68. Bulkley BH, Rouleau J, Strauss HW, Pitt B. Idiopathic hypertrophic 48. McKenna WJ, Franklin RC, Nihoyannopoulos P, Robinson KC, subaortic stenosis: Detection by thallium 201 myocardial perfusion Deanfield JE. Arrhythmia and prognosis in infants, children and imaging. N Engl J Med 1975; 293: 1113 – 1116. adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol 69. Suzuki Y, Kadota K, Nohara R, Tamaki S, Kambara H, Yoshida A, 1988; 11: 147 – 153. et al. Recognition of regional hypertrophy in hypertrophic cardio- 49. Spirito P, Rapezzi C, Autore C, Bruzzi P, Bellone P, Ortolani P, et myopathy using thallium-201 emission-computed tomography: al. Prognosis of asymptomatic patients with hypertrophic cardio- Comparison with two-dimensional echocardiography. Am J Car- myopathy and nonsustained ventricular tachycardia. Circulation diol 1984; 53: 1095 – 1102. 1994; 90: 2743 – 2747. 70. Ohtsuki K, Sugihara H, Kuribayashi T, Nakagawa M. Impairment

Circulation Journal Vol.80, March 2016 JCS Guidelines for Diagnosis and Treatment of Patients With HCM 771

of BMIPP accumulation at junction of ventricular septum and left Genet 1997; 34: 582 – 586. and right ventricular free walls in hypertrophic cardiomyopathy. J 92. Nakanishi T, Uemura S, Nakazawa M, Momma K, Takao A, Nucl Med 1999; 40: 2007 – 2013. Sekiguchi M, et al. Glycogen storage disease Type II (Pompe dis- 71. Kurata C, Tawarahara K, Taguchi T, Aoshima S, Kobayashi A, ease). Cardioangiology 1979; 5: 331 – 344 (in Japanese). Yamazaki N, et al. Myocardial emission computed tomography 93. Watkins H, McKenna WJ, Thierfelder L, Suk HJ, Anan R, with iodine-123-labeled betamethyl-branched fatty acid in patients O’Donoghue A, et al. Mutations in the genes for cardiac troponin with hypertrophic cardiomyopathy. J Nucl Med 1992; 33: 6 – 13. T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl 72. Shimizu M, Sugihara N, Kita Y, Shimizu K, Horita Y, Nakajima K, J Med 1995; 332: 1058 – 1064. et al. Long-term course and cardiac sympathetic nerve activity in 94. Genetic-medicine-related societies. Guidelines for genetic testing, patients with hypertrophic cardiomyopathy. Br Heart J 1992; 67: 2003. http://www.congre.co.jp/gene/guideline.html (in Japanese) 155 – 160. (accessed October 1, 2011). 73. Terai H, Shimizu M, Ino H, Yamaguchi M, Hayashi K, Sakata K, 95. World Health Organization Human Genetics Programme. WHO/ et al. Cardiac sympathetic nerve activity in patients with hypertro- HGN/ETH/004. Review of ethical issues in medical genetics. 2001. phic cardiomyopathy with malignant ventricular tachyarrhythmias. http://apps.who.int/iris/handle/10665/68512 (accessed October 1, J Nucl Cardiol 2003; 10: 304 – 310. 2011). 74. Dilsizian V, Bonow RO, Epstein SE, Fananapazir L. Myocardial 96. World Health Organization Human Genetics Programme. Proposed ischemia detected by thallium scintigraphy is frequently related to international guidelines on ethical issues in medical genetics and cardiac arrest and syncope in young patients with hypertrophic genetic services. 2001. http://www.congre.co.jp/gene/guideline. cardiomyopathy. J Am Coll Cardiol 1993; 22: 796 – 804. html (accessed October 1, 2011). 75. Yamada M, Elliott PM, Kaski JC, Prasad K, Gane JN, Lowe CM, 97. UNESCO. Universal Declaration on the Human Genome and et al. Dipyridamole stress thallium-201 perfusion abnormalities in Human Rights. 1997. http://www.mext.go.jp/unesco/009/005.htm patients with hypertrophic cardiomyopathy: Relationship to clinical (accessed October 1, 2011). presentation and outcome. Eur Heart J 1998; 19: 500 – 507. 98. UNESCO. International Declaration on Human Genetic Data. 2003. 76. Betocchi S, Bonow RO, Bacharach SL, Rosing DR, Maron BJ, http://www.mext.go.jp/unesco/009/005.htm (accessed October 1, Green MV. Isovolumic relaxation period in hypertrophic cardiomy- 2011). opathy: Assessment by radionuclide angiography. J Am Coll Car- 99. Japanese Ministry of Education, Culture, Sports, Science and Tech- diol 1986; 7: 74 – 81. nology; Japanese Ministry of Health, Labor and Welfare; Japanese 77. Chikamori T, Dickie S, Poloniecki JD, Myers MJ, Lavender JP, Ministry of Economy, Trade and Industry. Ethical guidelines for McKenna WJ. Prognostic significance of radionuclide-assessed research involving human genome and gene analysis (revised). diastolic function in hypertrophic cardiomyopathy. Am J Cardiol 2008. http://www.congre.co.jp/gene/guideline.html (in Japanese) 1990; 65: 478 – 482. (accessed October 1, 2011). 78. Yazaki Y, Isobe M, Hayasaka M, Tanaka M, Fujii T, Sekiguchi M. 100. The Japanese Association of Medical Sciences. Guidelines for ge- Cardiac sarcoidosis mimicking hypertrophic cardiomyopathy: netic testing and diagnosis in medical practice. 2011. http://jams. Clinical utility of radionuclide imaging for differential diagnosis. med.or.jp/guideline/genetics-diagnosis.pdf (in Japanese) (accessed Jpn Circ J 1998; 62: 465 – 468. February 1, 2012). 79. Hongo M, Hirayama J, Fujii T, Yamada H, Okubo S, Kusama S, et 101. Guidelines for Diagnosis and Treatment of Cardiovascular Dis- al. Early identification of amyloid heart disease by technetium-99 m- eases (2004–2005 Joint Working Groups Report). Guidelines for pyrophosphate scintigraphy: A study with familial amyloid poly- Genetic Test and Genetic Councelling in Cardiovascular Disease neuropathy. Am Heart J 1987; 113: 654 – 662. (JCS 2006). Circ J 2006; 70(Suppl IV): 1329 – 1375 (in Japanese). 80. Tadamura E, Tamaki N, Matsumori A, Magata Y, Yonekura Y, 102. Spirito P, Maron BJ. Relation between extent of left ventricular Nohara R, et al. Myocardial metabolic changes in hypertrophic hypertrophy and occurrence of sudden cardiac death in hypertro- cardiomyopathy. J Nucl Med 1996; 37: 572 – 577. phic cardiomyopathy. J Am Coll Cardiol 1990; 15: 1521 – 1526. 81. Nienaber CA, Gambhir SS, Mody FV, Ratib O, Huang SC, Phelps 103. Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, ME, et al. Regional myocardial blood flow and glucose utilization et al. An atypical variant of Fabry’s disease in men with left ven- in symptomatic patients with hypertrophic cardiomyopathy. Circu- tricular hypertrophy. N Engl J Med 1995; 333: 288 – 293. lation 1993; 87: 1580 – 1590. 104. von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hübner G, 82. Eriksson MJ, Sonnenberg B, Woo A, Rakowski P, Parker TG, Olsen EG, et al. An atypical variant of Fabry’s disease with mani- Wigle ED, et al. Long-term outcome in patients with apical hyper- festations confined to the myocardium. N Engl J Med 1991; 324: trophic cardiomyopathy. J Am Coll Cardiol 2002; 39: 638 – 645. 395 – 399. 83. Moon JC, Fisher NG, McKenna WJ, Pennell DJ. Detection of api- 105. Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, cal hypertrophic cardiomyopathy by cardiovascular magnetic reso- et al. Prevalence of Anderson-Fabry disease in male patients with nance in patients with non-diagnostic echocardiography. Heart late onset hypertrophic cardiomyopathy. Circulation 2002; 105: 2004; 90: 645 – 649. 1407 – 1411. 84. Moon JC, Reed E, Sheppard MN, Elkington AG, Ho SY, Burke M, 106. Chen YT. Glycogen storage diseases. In: Scriver CR, Beaudet AL, et al. The histologic basis of late gadolinium enhancement cardio- Sly WA, Valle D, editors. The metabolic and molecular bases of vascular magnetic resonance in hypertrophic cardiomyopathy. J Am inherited disease, 8th edn. McGraw-Hill, 2001: 1521 – 1552. Coll Cardiol 2004; 43: 2260 – 2264. 107. Maron BJ, Roberts WC, Arad M, Haas TS, Spirito P, Wright GB, 85. Ho CY, López B, Coelho-Filho OR, Lakdawala NK, Cirino AL, et al. Clinical outcome and phenotypic expression in LAMP2 car- Jarolim P, et al. Myocardial fibrosis as an early manifestation of diomyopathy. JAMA 2009; 301: 1253 – 1259. hypertrophic cardiomyopathy. N Engl J Med 2010; 363: 552 – 563. 108. Van Hove JL, Wevers RA, Van Cleemput J, Moerman P, Sciot R, 86. Moon JC, McKenna WJ, McCrohon JA, Elliott PM, Smith GC, Matthijs G, et al. Late-onset visceral presentation with cardiomy- Pennell DJ. Toward clinical risk assessment in hypertrophic cardio- opathy and without neurological symptoms of adult Sanfilippo A myopathy with gadolinium cardiovascular magnetic resonance. J syndrome. Am J Med Genet A 2003; 118A: 382 – 387. Am Coll Cardiol 2003; 41: 1561 – 1567. 109. Musante L, Kehl HG, Majewski F, Meinecke P, Schweiger S, 87. Olivotto I, Maron MS, Autore C, Lesser JR, Rega L, Casolo G, et Gillessen-Kaesbach G, et al. Spectrum of mutations in PTPN11 and al. Assessment and significance of left ventricular mass by cardio- genotype-phenotype correlation in 96 patients with Noonan syn- vascular magnetic resonance in hypertrophic cardiomyopathy. J Am drome and five patients with cardiofacio-cutaneous syndrome. Eur Coll Cardiol 2008; 52: 559 – 566. J Hum Genet 2003; 11: 201 – 206. 88. O’Hanlon R, Grasso A, Roughton M, Moon JC, Clark S, Wage R, 110. Ichida F, Hamamichi Y, Miyawaki T, Ono Y, Kamiya T, Akagi T, et al. Prognostic significance of myocardial fibrosis in hypertrophic et al. Clinical features of isolated noncompaction of the ventricular cardiomyopathy. J Am Coll Cardiol 2010; 56: 867 – 874. myocardium: Long-term clinical course, hemodynamic properties, 89. Bruder O, Wagner A, Jensen CJ, Schneider S, Ong P, Kispert EM, and genetic background. J Am Coll Cardiol 1999; 34: 233 – 240. et al. Myocardial scar visualized by cardiovascular magnetic reso- 111. Ichida F, Tsubata S, Bowles KR, Haneda N, Uese K, Miyawaki T, nance imaging predicts major adverse events in patients with hy- et al. Novel gene mutations in patients with left ventricular non- pertrophic cardiomyopathy. J Am Coll Cardiol 2010; 56: 875 – 887. compaction or Barth syndrome. Circulation 2001; 103: 1256 – 1263. 90. Jyouo K. Syndromes and cardiac disease. In: Takao A, Nakazawa 112. Towbin JA. Hypertrophic cardiomyopathy. Pacing Clin Electro- M, Momma K, Nakanishi T, editors. Clinical developmental cardi- physiol 2009; 32(Suppl 2): S23 – S31. ology. Tokyo: Chugai-Igakusha, 2001: 834 – 847 (in Japanese). 113. Coppin BD, Temple IK. Multiple lentigines syndrome (LEOPARD 91. Coppin BD, Temple IK. Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis). J Med syndrome or progressive cardiomyopathic lentiginosis). J Med Genet 1997; 34: 582 – 586.

Circulation Journal Vol.80, March 2016 772 JCS Joint Working Group

114. Berg RA, Kaplan AM, Jarrett PB, Molthan ME. Friedreich’s ataxia J Heart Valve Dis 1998; 7: 355 – 357. with acute cardiomyopathy. Am J Dis Child 1980; 134: 390 – 393. 134. Paz R, Jortner R, Tunick PA, Sclarovsky S, Eilat B, Perez JL, et al. 115. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, The effect of the ingestion of ethanol on obstruction of the left Arnett D, et al. Contemporary definitions and classification of the ventricular outflow tract in hypertrophic cardiomyopathy. N Engl J cardiomyopathies: An American Heart Association Scientific State- Med 1996; 335: 938 – 941. ment from the Council on Clinical Cardiology, Heart Failure and 135. Kodama K, Hamada M, Kazatani Y, Matsuzaki K, Murakami E, Transplantation Committee; Quality of Care and Outcomes Re- Shigematsu Y, et al. Clinical characteristics in Japanese patients search and Functional Genomics and Translational Biology Inter- with coexistent hypertrophic cardiomyopathy and coronary vaso- disciplinary Working Groups; and Council on Epidemiology and spasm. Angiology 1998; 49: 849 – 855. Prevention. Circulation 2006; 113: 1807 – 1816. 136. Dajani AS, Taubert KA, Wilson W, Bolger AF, Bayer A, Ferrieri 116. Nishikawa T, Ishiyama S, Shimojo T, Takeda K, Kasajima T, P, et al. Prevention of bacterial endocarditis: Recommendations by Momma K. Hypertrophic cardiomyopathy in Noonan syndrome. the American Heart Association. JAMA 1997; 277: 1794 – 1801. Acta Paediatr Jpn 1996; 38: 91 – 98. 137. Spirito P, Rapezzi C, Bellone P, Betocchi S, Autore C, Conte MR, 117. Gutgesell HP, Mullins CE, Gillette PC, Speer M, Rudolph AJ, et al. Infective endocarditis in hypertrophic cardiomyopathy: Prev- McNamara DG. Transient hypertrophic subaortic stenosis in infants alence, incidence, and indications for antibiotic prophylaxis. Circu- of diabetic mothers. J Pediatr 1976; 89: 120 – 125. lation 1999; 99: 2132 – 2137. 118. Kurosaki K, Amano M, Mitsushita N, Fukuoka T, Tanaka Y, Saito 138. Kubo T, Kitaoka H, Okawa M, Hirota T, Hayato K, Yamasaki N, A. Cardiac involvement and sudden death in pediatric patients with et al. Clinical impact of atrial fibrillation in patients with hypertro- congenital myotonic dystrophy. Ped Cardiol Card Surg 2000; 16: phic cardiomyopathy: Results from Kochi RYOMA Study. Circ J 879 – 886 (in Japanese). 2009; 73: 1599 – 1605. 119. Maron BJ, Isner JM, McKenna WJ. 26th Bethesda conference 139. Maron BJ, Olivotto I, Bellone P, Conte MR, Cecchi F, Flygenring recommendation for determing eligibility forcompetition in athletes BP, et al. Clinical profile of stroke in 900 patients with hypertrophic with cardiovascular abnormalities: Taskforce 3: Hypertrophic car- cardiomyopathy. J Am Coll Cardiol 2002; 39: 301 – 307. diomyopathy, myocarditis and othermyopericardial diseases, and 140. Fujiki N. Genetic counseling. In: Imura H, Takahisa F, Ogata E, mitral valve prolapse. J Am Coll Cardiol 1994; 24: 845 – 899. Tarui S, editors. Integrated handbook of internal medicine. Volume 120. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, 1. Tokyo: Nakayama Shoten Co., Ltd. 1997: 292 – 299 (in Japanese). Udelson JE. Task Force 4: HCM and other cardiomyopathies, mi- 141. Maron BJ, Seidman JG, Seidman CE. Proposal for contemporary tral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll screening strategies in families with hypertrophic cardiomyopathy. Cardiol 2005; 45: 1340 – 1345. J Am Coll Cardiol 2004; 44: 2125 – 2132. 121. Maron BJ, Chaitman BR, Ackerman MJ, Bayés de Luna A, Corrado 142. Spirito P, Seidman CE, McKenna WJ, Maron BJ. The management D, Crosson JE, et al; Working Groups of the American Heart As- of hypertrophic cardiomyopathy. N Engl J Med 1997; 336: 775 – sociation Committee on Exercise, Cardiac Rehabilitation, and Pre- 785. vention; Councils on Clinical Cardiology and Cardiovascular Dis- 143. Maron BJ. Hypertrophic cardiomyopathy. Lancet 1997; 350: 127 – ease in the Young. Recommendations for physical activity and 133. recreational sports participation for young patients with genetic 144. Wynne J, Braunwald E. The cardiomyopathies and myocarditides. cardiovascular diseases. Circulation 2004; 109: 2807 – 2816. In: Braunwald E, Zipes DP, Libby P, editors. Heart disease: A 122. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn Textbook of Cardiovascular Medicine, 6th edn. WB Saunders, HJ, Seidman CE, et al. American College of Cardiology/European 2001: 1760 – 1774. Society of Cardiology clinical expert consensus document on hy- 145. McKenna WJ, Behr ER. Hypertrophic cardiomyopathy: Manage- pertrophic cardiomyopathy: A report of the American College of ment, risk stratification, and prevention of sudden death. Heart Cardiology Foundation Task Force on Clinical Expert Consensus 2002; 87: 169 – 176. Documents and the European Society of Cardiology Committee for 146. Effect of enalapril on mortality and the development of heart failure Practice Guidelines. J Am Coll Cardiol 2003; 42: 1687 – 1713. in asymptomatic patients with reduced left ventricular ejection frac- 123. Kondou N, Sakurai K, Toyoda T, Yokoyama M, Daimon M, tions. The SOLVD Investigattors. N Engl J Med 1992; 327: Fujimoto Y, et al. Cibenzoline relieves the pressure gradient of the 685 – 691. left ventricular outflow tract stenosis with hypertrophic cardiomy- 147. Effect of enalapril on survival in patients with reduced left ven- opathy during bicycle ergometry. Heart 2001; 33: 841 – 846 (in tricular ejection fractions and congestive heart failure. The SOLVD Japanese). Investigators. N Engl J Med 1991; 325: 293 – 302. 124. Johnston BL, Fletcher GF. Dynamic electrocardiographic recording 148. Effects of enalapril on mortality in severe congestive heart failure. during sexual activity in recent myocardial infarction and revascu- Results of the Cooperative North Scandinavian Enalapril Survival larization patients. Am Heart J 1979; 98: 736 – 741. Study (CONSENSUS). The CONSENSUS Trial Study Group. N 125. DeBusk R, Drory Y, Goldstein I, Jackson G, Kaul S, Kimmel SE, Engl J Med 1987; 316: 1429 – 1435. et al. Management of sexual dysfunction in patients with cardiovas- 149. Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz cular disease: Recommendations of The Princeton Consensus JD, Massie BM, et al. Comparative effects of low and high doses Panel. Am J Cardiol 2000; 86: 175 – 181. of the angiotensin-converting enzyme inhibitor, lisinopril, on mor- 126. Kostis JB, Jackson G, Rosen R, Barrett-Connor E, Billups K, bidity and mortality in chronic heart failure: ATLAS Study Group. Burnett AL, et al. Sexual dysfunction and cardiac risk (the Second Circulation 1999; 100: 2312 – 2318. Princeton Consensus Conference). Am J Cardiol 2005; 96: 313 – 150. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, 321. Camm AJ, et al. Effect of losartan compared with captopril on 127. Autore C, Conte MR, Piccininno M, Bernabò P, Bonfiglio G, mortality in patients with symptomatic heart failure: Randomised Bruzzi P, et al. Risk associated with pregnancy in hypertrophic trial--the Losartan Heart Failure Survival Study ELITE II. Lancet cardiomyopathy. J Am Coll Cardiol 2002; 40: 1864 – 1869. 2000; 355: 1582 – 1587. 128. Thaman R, Varnava A, Hamid MS, Firoozi S, Sachdev B, Condon 151. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, M, et al. Pregnancy related complications in women with hypertro- Michelson EL, et al; CHARM Investigators and Committees. Ef- phic cardiomyopathy. Heart 2003; 89: 752 – 756. fects of candesartan on mortality and morbidity in patients with 129. Kolibash AJ, Ruiz DE, Lewis RP. Idiopathic hypertrophic subaortic chronic heart failure: The CHARM-Overall programme. Lancet 2003; stenosis in pregnancy. Ann Intern Med 1975; 82: 791 – 794. 362: 759 – 766. 130. Kazimuddin M, Vashist A, Basher AW, Brown EJ Jr, Alhaddad IA. 152. Matsumori A; Assessment of Response to Candesartan in Heart Pregnancyinduced severe left ventricular systolic dysfunction in a Failure in Japan (ARCH-J) Study Investigators. Efficacy and safety patient with hypertrophic cardiomyopathy. Clin Cardiol 1998; 21: of oral candesartan cilexetil in patients with congestive heart fail- 848 – 850. ure. Eur J Heart Fail 2003; 5: 669 – 677. 131. Pelliccia F, Cianfrocca C, Gaudio C, Reale A. Sudden death during 153. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. pregnancy in hypertrophic cardiomyopathy. Eur Heart J 1992; 13: A randomized trial of the angiotensin-receptor blocker valsartan in 421 – 423. chronic heart failure. N Engl J Med 2001; 345: 1667 – 1675. 132. Oakley GD, McGarry K, Limb DG, Oakley CM. Management of 154. Guidelines for the Diagnosis and Treatment of Cardiovascular pregnancy in patients with hypertrophic cardiomyopathy. Br Med Diseases (2009 Joint Working Groups Report). Guidelines for J 1979; 1: 1749 – 1750. Treatment of Chronic Heart Failure (JCS 2010). http://www.j-circ. 133. Wilansky S, Belcik T, Osborn R, Carpenter R. Hypertrophic car- or.jp/guideline/pdf/JCS2010_matsuzaki_h.pdf (in Japanese) (ac- diomyopathy in pregnancy: The use of two-dimensional and cessed October 1, 2011). Doppler echocardiography during labor and delivery: A case report. 155. Maron BJ. Hypertrophic cardiomyopathy: A systematic review.

Circulation Journal Vol.80, March 2016 JCS Guidelines for Diagnosis and Treatment of Patients With HCM 773

JAMA 2002; 287: 1308 – 1320. implantation of cardiac pacemakers and antiarrhythmia devices: 156. Hamada M, Shigematsu Y, Ikeda S, Hara Y, Okayama H, Kodama Summary article: A report of the American College of Cardiology/ K, et al. Class Ia antiarrhythmic drug cibenzoline: A new approach American Heart Association Task Force on Practice Guidelines to the medical treatment of hypertrophic obstructive cardiomyopa- (ACC/AHA/NASPE Committee to Update the 1998 Pacemeker thy. Circulation 1997; 96: 1520 – 1524. Guidelines). Circulation 2002; 106: 2145 – 2161. 157. Suwa M, Hirota Y, Kawamura K. Improvement in left ventricular 174. McAlister FA, Ezekowitz J, Hooton N, Vandermeer B, Spooner C, diastolic function during intravenous and or aldiltiaze therapy in Dryden DM, et al. Cardiac resynchronization therapy for patients patient with hypertrophic cardiomyopathy: An echocardiographic with left ventricular systolic dysfunction: A systematic review. study. Am J Cardiol 1984; 54: 1047 – 1053. JAMA 2007; 297: 2502 – 2514. 158. Betocchi S, Cannon RO 3rd, Watson RM, Bonow RO, Ostrow HG, 175. Rivero-Ayerza M, Theuns DA, Garcia-Garcia HM, Boersma E, Epstein SE, et al. Effects of sublingual nifedipine on hemodynam- Simoons M, Jordaens LJ. Effects of cardiac resynchronization ics and systolic and diastolic function in patients with hypertrophic therapy on overall mortality and mode of death: A meta-analysis of cardiomyopathy. Circulation 1985; 72: 1001 – 1007. randomized controlled trials. Eur Heart J 2006; 27: 2682 – 2688. 159. McKenna WJ, Harris L, Rowland E, Kleinebenne A, Krikler DM, 176. Sigwart U. Non-surgical myocardial reduction for hypertrophic Oakley CM, et al. Amiodarone for long-term management of pa- obstructive cardiomyopathy. Lancet 1995; 346: 211 – 214. tients with hypertrophic cardiomyopathy. Am J Cardiol 1984; 54: 177. Knight C, Kurbaan AS, Seggewiss H, Henein M, Gunning M, 802 – 810. Harrington D, et al. Non-surgical septal reduction for hypertrophy 160. Braunwald E, Seidman CE, Sigwart U. Contemporary evaluation obstructive cardiomyopathy: Outcome in the first series of patients. and management of hypertrophic cardiomyopathy. Circulation 2002; Circulation 1997; 95: 2075 – 2081. 106: 1312. 178. Seggewiss H, Gleichmann U, Faber L, Fassbender D, Schmidt HK, 161. Ho CY, Seidman CE. A contemporary approach to hypertrophic Strick S. Percutaneous transluminal septal myocardial ablation in cardiomyopathy. Circulation 2006; 113: e858 – e862, doi:10.1161/ hypertrophic obstructive cardiomyopathy: Acute results and CIRCULATIONAHA.105.591982. 3-months followup in 25 patients. J Am Coll Cardiol 1998; 31: 162. O’Mahony C, Lambiase PD, Quarta G, Cardona M, Calcagnino M, 252 – 258. Tsovolas K, et al. The long-term survival and the risks and benefits 179. Takayama M. The therapeutic effect and clinical significance of of implantable cardioverter defibrillators in patients with hypertro- percutaneous transluminal septal myocardial ablation (PTSMA). phic cardiomyopathy. Heart 2010; 98: 116 – 125. Heart 2006; 38: 330 – 334 (in Japanese). 163. Guidelines for the Diagnosis and Treatment of Cardiovascular 180. Faber L, Seggewiss H, Gleichmann U. Percutaneous transluminal Diseases (2010 Joint Working Groups Report). Guidelines for Non- septal myocardial ablation in hypertrophic cardiomyopathy: Results Pharmacotherapy of Cardiac Arrhythmias (JCS 2011). http:// with respect to inttraprocedual myocardial contrast echocardiogra- www.j-circ.or.jp/guideline/pdf/JCS2011_okumura_h.pdf (in Japanese) phy. Circulation 1998; 98: 2415 – 2421. (accessed February 1, 2012). 181. Matsumoto H, Takayama M. Acute and long-term result of PTSMA. 164. Morrow AG. Hypertrophic subaortic stenosis: Operative methods Circ J 2006; 70-I: 124. utilized to relieve left ventricular outflow obstruction. J Thorac 182. Tsuchikane E, Takeda Y, Kobayashi T, Yachiku K, Nasu K, Cardiovasc Surg 1978; 76: 423 – 430. Kobayashi Y, et al. Percutaneous transluminal septal myocardial 165. Robbins RC, Stinson EB. Long-term results of left ventricular ablation for hypertrophic obstructive cardiomyopathy. Circ J 2003; myotomy and myoectomy for obstructive hypertrophic cardiomy- 67: 763 – 767. opathy. J Thorac Cardiovasc Surg 1996; 111: 586 – 594. 183. Sorajja P, Valeti U, Nishimura RA, Ommen SR, Rihal CS, Gersh 166. Merrill WH, Friesinger GC, Graham TP Jr, Byrd BF 3rd, BJ, et al. Outcome of alcohol septal ablation for obstructive hyper- Drinkwater DC Jr, Christian KG, et al. Long-lasting improvement trophic cardiomyopathy. Circulation 2008; 118: 131 – 139. after septal myectomy for hypertrophic obstructive cardiomyopa- 184. ten Cate FJ, Soliman OI, Michels M, Theuns DA, de Jong PL, thy. Ann thorac Surg 2000; 69: 1732 – 1736. Geleijnse ML, et al. Long-term outcome of alcohol septal ablation 167. Ueda Y, Fujii Y, Kuwano H. Thoracic and cardiovascular surgery in patients with obstructive hypertrophic cardiomyopathy: A word in Japan during 2007: Annual report by the Japanese Association fo of caution. Circ Heart Fail 2010; 3: 362 – 369. Thoracic Surgery. Gen Thorac Cardiovasc Surg 2009; 57: 488 – 185. Jensen MK, Almaas VM, Jacobsson L, Hansen PR, Havndrup O, 513. Aakhus S, et al. Long-term outcome of percutaneous transluminal 168. Fananapazir L, Cannon RO 3rd, Tripodi D, Panza JA. Impact of septal myocardial ablation in hypertrophic obstructive cardiomy- dual-chamber permanent pacing in patients with obstructive hyper- opathy: A Scandinavian multicenter study. Circ Cardiovasc Interv trophic cardiomyopathy with symptoms refractory to verapamil and 2011; 4: 256 – 265. beta-adrenergic blocker therapy. Circulation 1992; 85: 2149 – 2161. 186. Spirito P, Maron BJ. Perspectives on the role of new treatment 169. Jeanrenaud X, Goy JJ, Kappenberger L. Effects of dualchamber strategies in hypertrophic obstructive cardiomyopathy. J Am Coll pacing in hypertrophic obstructive cardiomyopathy. Lancet 1992; Cardiol 1999; 33: 1071 – 1075. 339: 1318 – 1323. 187. Guide for the use of the School Activity Management Table for 170. Kappenberger L, Linde C, Daubert C, McKenna W, Meisel E, Children with Heart Disease; Guide for the use of the School Activ- Sadoul N, et al. Pacing in hypertrophic obstructive cardiomyopa- ity Management Table for Children with Renal Disease: For schools thy: A randomized crossover study. PIC Study Group. Eur Heart J and school physicians, the 2011 revision. The Japanese Society of 1997; 18: 1249 – 1256. School Health. 2013: 3 – 11 (in Japanese). 171. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson 188. Theodoro DA, Danielson GK, Feldt RH, Anderson BJ. Hypertro- ME, Kieval RS. Assessment of permanent dual-chamber pacing as phic obstructive cardiomyopathy in pediatric patients: Results of a treatment for drugrefractory symptomatic patients with obstruc- surgical treatment. J Thorac Cardiovasc Surg 1996; 112: 1589 – 1597; tive hypertrophic cardiomyopathy: A randomized, double-blind, discussion 1597 – 1599. crossover study (M-PATHY). Circulation 1999; 99: 2927 – 2933. 189. Vouhé PR, Ouaknine R, Poulain H, Vernant F, Mauriat P, Pouard 172. Nishimura RA, Trusty JM, Hayes DL, Ilstrup DM, Larson DR, P, et al. Diffuse subaortic stenosis: Modified Konno procedures Hayes SN, et al. Dual-chamber pacing for patients with hyper- with aortic valve preservation. Eur J Cardiothorac Surg 1993; 7: tyrophic obstructive cardiomyopathy: A randomized doubleblind 132 – 136. crossover trial. J Am Coll Cardiol 1997; 29: 435 – 441. 190. Cohn LH, Trehan H, Collins JJ. Long-term follow-up of patients 173. Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, undergoing myotomy-myectomy for obstructive hypertrophic car- Hlatky MA, et al. ACC/AHA/NASPE 2002 guideline update for diomyopathy. Am J Cardiol 1992; 70: 657 – 660.

Appendix Chair: Women’s Medical University • Yoshinori Doi, Cardiomyopathy Center, Chikamori Hospital • Mareomi Hamada, Uwajima City Hospital • Fukiko Ichida, Department of Pediatrics, Faculty of Medicine, Univer- Members: sity of Toyama • Taishiro Chikamori, Second Department of Internal Medicine (Circula- • Hiroya Kawai, Division of Cardiovascular Medicine, Himeji Cardio- tory Organs), Tokyo Medical University vascular Center • Nobuhisa Hagiwara, Department of Cardiovascular Medicine, Tokyo • Masatoshi Kawana, Department of Cardiology, Aoyama Hospital,

Circulation Journal Vol.80, March 2016 774 JCS Joint Working Group

Tokyo Women’s Medical University Kochi Medical School, Kochi University • Tohru Masuyama, Cardiovascular Division, Department of Internal • Yuichiro Minami, Department of Cardiovascular Medicine, Tokyo Medicine, Hyogo College of Medicine Women’s Medical University • Satoshi Nakatani, Division of Health Sciences, Medical Ultrasonics, • Toshio Nishikawa, Department of Surgical Pathology, Tokyo Women’s Osaka University Graduate School of Medicine Medical University • Morimasa Takayama, Department of Cardiology, Sakakibara Heart • Tsuyoshi Shiga, Department of Cardiovascular Medicine, Tokyo Institute Women’s Medical University • Chuwa Tei, Waon Therapy Research Institute • Shunji Sano, Department of Cardiovascular Surgery, Okayama Univer- Independent Assessment Committee: sity Graduate School of Medicine, Dentistry and Pharmaceutical • Hisayoshi Fujiwara, Hyogo Prefectural Amagasaki General Medical Science Center • Yasuki Kihara, Department of Cardiovascular Medicine, Hiroshima Collaborators: University Graduate School of Biomedical Sciences • Ryuichiro Anan, Department of Cardiovascular Medicine, National • Akinori Kimura, Division of Pathophysiology, Department of Molecu- Hospital Organization Miyakonojo Hospital lar Pathogenesis, Medical Research Institute, Tokyo Medical and • Kei Inai, Department of Pediatric Cardiology, Tokyo Women’s Medi- Dental University cal University • Akira Kitabatake, Hiraoka Hospital • Hiroaki Kitaoka, Department of Cardiology, Neurology and Aging • Yoshinori Koga, Hagiwara Central Hospital Science, Kochi Medical School, Kochi University • Junichi Yoshikawa, Nishinomiya Watanabe Cardiovascular Center • Toru Kubo, Department of Cardiology, Neurology and Aging Science, (The affiliations of the members are as of July 2015)

Circulation Journal Vol.80, March 2016