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2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy

A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

      Preamble

      It is essential that the medical profession play a central role in critically evaluating the evidence related to drugs, devices, and procedures for the detection, management, or prevention of disease. Properly applied, rigorous, expert analysis of the available data documenting absolute and relative benefits and risks of these therapies and procedures can improve the effectiveness of care, optimize patient outcomes, and favorably fnect the cost of care by focusing resources on the most effective strategies. One important use of such data is the production of clinical practice guidelines that, in turn, can provide a foundation for a variety of other applications such as performance measures, appropriateness use criteria, clinical decision support tools, and quality improvement tools.
      The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have jointly engaged in the production of guidelines in the area of cardiovascular disease since 1980. The ACCF/AHA Task Force on Practice Guidelines (Task Force) is charged with developing, updating, and revising practice guidelines for cardiovascular diseases and procedures, and the Task Force directs and oversees this effort. Writing committees are charged with assessing the evidence as an independent group of authors to develop, update, or revise recommendations for clinical practice.
      Experts in the subject under consideration have been selected from both organizations to examine subject-specific data and write guidelines in partnership with representatives from other medical practitioner and specialty groups. Writing committees are specifically charged to perform a formal literature review, weigh the strength of evidence for or against particular tests, treatments, or procedures, and include estimates of expected health outcomes where data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that may influence the choice of tests or therapies are considered. When available, information from studies on cost is considered, but data on efficacy and clinical outcomes constitute the primary basis for recommendations in these guidelines.
      In analyzing the data and developing the recommendations and supporting text, the writing committee used evidence-based methodologies developed by the Task Force, which are described elsewhere.

      ACCF/AHA Task Force on Practice Guidelines. Methodology Manual and Policies from the ACCF/AHA Task Force on Practice Guidelines. Available at: http://assets.cardiosource.com/Methodology_Manual_for_ACC_AHA_Writing_Committees.pdf and http://circ.ahajournals.org/site/manual/index.xhtml. Accessed July 11, 2011.

      The committee reviewed and ranked evidence supporting current recommendations with the weight of evidence ranked as Level A if the data were derived from multiple randomized clinical trials (RCTs) or meta-analyses. The committee ranked available evidence as Level B when data were derived from a single RCT or nonrandomized studies. Evidence was ranked as Level C when the primary source of the recommendation was consensus opinion, case studies, or standard of care. In the narrative portions of these guidelines, evidence is generally presented in chronological order of development. Studies are identified as observational, retrospective, prospective, or randomized when appropriate. For certain conditions for which inadequate data are available, recommendations are based on expert consensus and clinical experience and ranked as Level C. An example is the use of penicillin for pneumococcal pneumonia, for which there are no RCTs and treatment is based on clinical experience. When recommendations at Level C are supported by historical clinical data, appropriate references (including clinical reviews) are cited if available. For issues where sparse data are available, a survey of current practice among the clinicians on the writing committee was the basis for Level C recommendations and no references are cited. The schema for Classification of Recommendations and Level of Evidence is summarized in Table 1, which also illustrates how the grading system provides an estimate of the size and the certainty of the treatment effect. A new addition to the ACCF/AHA methodology is separation of the Class III recommendations to delineate whether the recommendation is determined to be of “no benefit” or associated with “harm” to the patient. In addition, in view of the increasing number of comparative effectiveness studies, comparator verbs and suggested phrases for writing recommendations for the comparative effectiveness of one treatment/strategy with respect to another for Class of Recommendation I and IIa, Level of Evidence A or B only have been added.
      Table 1Applying classification of recommendation and level of evidence
      Figure thumbnail fx1
      A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. †For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated.
      The Task Force makes every effort to avoid actual, potential, or perceived conflicts of interest that may arise as a result of relationships with industry and other entities (RWI) among the writing committee. Specifically, all members of the writing committee, as well as peer reviewers of the document, are required to disclose all relevant relationships and those 12 months prior to initiation of the writing effort. The policies and procedures for RWI for this guideline were those in effect at the initial meeting of this committee (March 28, 2009), which included 50% of the writing committee with no relevant RWI. All guideline recommendations require a confidential vote by the writing committee and must be approved by a consensus of the members voting. Members who were recused from voting are indicated on the title page of this document with detailed information included in Appendix 1. Members must recuse themselves from voting on any recommendations where their RWI apply. If a writing committee member develops a new RWI during his/her tenure, he/she is required to notify guideline stfn in writing. These statements are reviewed by the Task Force and all members during each conference call and/or meeting of the writing committee and are updated as changes occur. For detailed information regarding guideline policies and procedures, please refer to the ACCF/AHA methodology and policies manual.

      ACCF/AHA Task Force on Practice Guidelines. Methodology Manual and Policies from the ACCF/AHA Task Force on Practice Guidelines. Available at: http://assets.cardiosource.com/Methodology_Manual_for_ACC_AHA_Writing_Committees.pdf and http://circ.ahajournals.org/site/manual/index.xhtml. Accessed July 11, 2011.

      RWI pertinent to this guideline for authors and peer reviewers are disclosed in Appendixes 1 and 2, respectively. Comprehensive disclosure information for the Task Force is also available online at http://www.cardiosource.org/ACC/About-ACC/Leadership/Guidelines-and-Documents-Task-Forces.aspx. The work of the writing committee was supported exclusively by the ACCF and AHA without commercial support. Writing committee members volunteered their time for this effort.
      The ACCF/AHA practice guidelines address patient populations (and healthcare providers) residing in North America. As such, drugs that are currently unavailable in North America are discussed in the text without a specific class of recommendation. For studies performed in large numbers of subjects outside of North America, each writing group reviews the potential impact of different practice patterns and patient populations on the treatment effect and on the relevance to the ACCF/AHA target population to determine whether the findings should inform a specific recommendation.
      The ACCF/AHA practice guidelines are intended to assist healthcare providers in clinical decision making by describing a range of generally acceptable approaches for the diagnosis, management, and prevention of specific diseases or conditions. These practice guidelines represent a consensus of expert opinion after a thorough review of the available current scientific evidence and are intended to improve patient care. The guidelines attempt to define practices that meet the needs of most patients in most circumstances. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and patient in light of all the circumstances presented by that patient. Thus, there are situations in which deviations from these guidelines may be appropriate. Clinical decision making should consider the quality and availability of expertise in the area where care is provided. When these guidelines are used as the basis for regulatory or payer decisions, the goal should be improvement in quality of care. The Task Force recognizes that situations arise for which additional data are needed to better inform patient care; these areas will be identified within each respective guideline when appropriate.
      Prescribed courses of treatment in accordance with these recommendations are effective only if they are followed. Because lack of patient understanding and adherence may adversely fnect outcomes, physicians and other healthcare providers should make every effort to engage the patient’s active participation in prescribed medical regimens and lifestyles.
      The guideline will be reviewed annually by the Task Force and considered current unless it is updated, revised, or withdrawn from distribution.
      Guidelines are official policy of both the ACCF and AHA.
      Alice K. Jacobs, MD, FACC, FAHA
      Chair, ACCF/AHA Task Force on Practice Guidelines

      1. Introduction

      1.1 Methodology and Evidence Review

      The recommendations listed in this document are, whenever possible, evidence based. An extensive evidence review was conducted through January 2011. Searches were limited to studies, reviews, and other evidence conducted in human subjects and published in English. Key search words included, but were not limited to, hypertrophic cardiomyopathy (HCM), surgical myectomy, ablation, exercise, sudden cardiac death (SCD), athletes, dual-chamber pacing, left ventricular outflow tract (LVOT) obstruction, alcohol septal ablation, automobile driving and implantable cardioverter-defibrillators (ICDs), catheter ablation, defibrillators, genetics, genotype, medical management, magnetic resonance imaging, pacing, permanent pacing, phenotype, pregnancy, risk stratification, sudden death in athletes, surgical septal myectomy, and septal reduction. Additionally, the committee reviewed documents related to the subject matter previously published by the ACCF and AHA. References selected and published in this document are representative and not all-inclusive.
      To provide clinicians with a comprehensive set of data, whenever deemed appropriate or when published, the absolute risk difference and number needed to treat or harm are provided in the guideline, along with confidence intervals and data related to the relative treatment effects, such as odds ratio, relative risk, hazard ratio, or incidence rate ratio.

      1.2 Organization of the Writing Committee

      The committee was composed of physicians and cardiac surgeons with expertise in HCM, invasive cardiology, noninvasive testing and imaging, pediatric cardiology, electrophysiology, and genetics. The committee included representatives from the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons.

      1.3 Document Review and Approval

      This document was reviewed by 2 outside reviewers nominated by both the ACCF and AHA, as well as 2 reviewers each from the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. Other content reviewers included members from the ACCF Adult Congenital and Pediatric Cardiology Council, ACCF Surgeons’ Scientific Council, and ACCF Interventional Scientific Council. All information on reviewers’ RWI was distributed to the writing committee and is published in this document (Appendix 2).
      This document was approved for publication by the governing bodies of the ACCF and the AHA and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.

      1.4 Scope of the Guideline

      Although there are reports of this disease dating back to the 1800s, the first modern pathologic description was provided over 50 years ago by Teare
      • Teare D.
      Asymmetrical hypertrophy of the heart in young adults.
      and the most important early clinical report by Braunwald et al in 1964.
      • Braunwald E.
      • Lambert C.T.
      • Rockoff S.D.
      • et al.
      Idiopathic hypertrophic subaortic stenosis, I: a description of the disease based upon an analysis of 64 patients.
      Since then, there has been a growing understanding of the complexity and diversity of the underlying genetic substrate, the clinical phenotype, natural history, and approaches to treatment.
      The impetus for the guideline is based on an appreciation of the frequency of this clinical entity and a realization that many aspects of clinical management, including the use of diagnostic modalities and genetic testing, lack consensus. Moreover, the emergence of 2 different approaches to septal reduction therapy (septal myectomy and alcohol septal ablation) in addition to the ICD has created considerable controversy. The discussion and recommendations about the various diagnostic modalities apply to patients with established HCM and to a variable extent to patients with a high index of suspicion of the disease.
      Although the Task Force was aware of the lack of high levels of evidence regarding HCM provided by clinical trials, it was believed that a guideline document based on expert consensus that outlines the most important diagnostic and management strategies would be helpful.
      To facilitate ease of use, it was decided that recommendations in the pediatric and adolescent age groups would not appear as a separate section but instead would be integrated into the overall content of the guideline where relevant.

      2. Prevalence/Nomenclature/Differential Diagnosis

      2.1 Prevalence

      HCM is a common genetic cardiovascular disease. In addition, HCM is a global disease,
      • Maron B.J.
      Hypertrophic cardiomyopathy: an important global disease.
      with epidemiological studies from several parts of the world
      • Zou Y.
      • Song L.
      • Wang Z.
      • et al.
      Prevalence of idiopathic hypertrophic cardiomyopathy in China: a population-based echocardiographic analysis of 8080 adults.
      reporting a similar prevalence of left ventricular (LV) hypertrophy, the quintessential phenotype of HCM, to be about 0.2% (ie, 1:500) in the general population, which is equivalent to at least 600,000 people fnected in the United States.
      • Maron B.J.
      • Gardin J.M.
      • Flack J.M.
      • et al.
      Prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiographic analysis of 4111 subjects in the CARDIA Study Coronary Artery Risk Development in (Young) Adults.
      This estimated frequency in the general population appears to exceed the relatively uncommon occurrence of HCM in cardiology practices, implying that most fnected individuals remain unidentified, probably in most cases without symptoms or shortened life expectancy.

      2.2 Nomenclature

      2.2.1 Historical Context

      Although HCM is the preferred nomenclature to describe this disease,
      • Maron B.J.
      • Epstein S.E.
      Hypertrophic cardiomyopathy: a discussion of nomenclature.
      confusion over the names used to characterize the entity of HCM has arisen over the years. At last count, >80 individual names, terms, and acronyms have been used (most by early investigators) to describe HCM.
      • Maron B.J.
      • Epstein S.E.
      Hypertrophic cardiomyopathy: a discussion of nomenclature.
      Furthermore, nomenclature that was popular in the 1960s and 1970s, such as IHSS (idiopathic hypertrophic subaortic stenosis) or HOCM (hypertrophic obstructive cardiomyopathy), is potentially confusing by virtue of the inference that LVOT is an invariable and obligatory component of the disease. In fact, fully one third of patients have no obstruction either at rest or with physiologic provocation.
      • Maron M.S.
      • Olivotto I.
      • Zenovich A.G.
      • et al.
      Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction.
      Although terms such as IHSS and HOCM persist occasionally in informal usage, they now rarely appear in the literature, whereas HCM, initially used in 1979, allows for both the obstructive and nonobstructive hemodynamic forms and has become the predominant formal term used to designate this disease.
      • Maron B.J.
      • Epstein S.E.
      Hypertrophic cardiomyopathy: a discussion of nomenclature.

      2.2.2 Clinical Definition and Differential Diagnosis

      The generally accepted definition of HCM, the clinical entity that is the subject of this guideline, is a disease state characterized by unexplained LV hypertrophy associated with nondilated ventricular chambers in the absence of another cardiac or systemic disease that itself would be capable of producing the magnitude of hypertrophy evident in a given patient,
      • Maron B.J.
      • Gardin J.M.
      • Flack J.M.
      • et al.
      Prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiographic analysis of 4111 subjects in the CARDIA Study Coronary Artery Risk Development in (Young) Adults.
      • Maron B.J.
      • Epstein S.E.
      Hypertrophic cardiomyopathy: a discussion of nomenclature.
      • Maron B.J.
      Hypertrophic cardiomyopathy: a systematic review.
      • Maron B.J.
      • McKenna W.J.
      • Danielson G.K.
      • et al.
      American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy.
      • Maron B.J.
      • Towbin J.A.
      • Thiene G.
      • et al.
      Contemporary definitions and classification of the cardiomyopathies: an American Heart Association scientific statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
      • Maron B.J.
      • Seidman C.E.
      • Ackerman M.J.
      • et al.
      How should hypertrophic cardiomyopathy be classified? What’s in a name? Dilemmas in nomenclature characterizing hypertrophic cardiomyopathy and left ventricular hypertrophy.
      with the caveat that patients who are genotype positive may be phenotypically negative without overt hypertrophy.
      • Maron B.J.
      • Yeates L.
      • Semsarian C.
      Clinical challenges of genotype positive (+)-phenotype negative (−) family members in hypertrophic cardiomyopathy.
      • Maron B.J.
      • Semsarian C.
      Emergence of gene mutation carriers and the expanding disease spectrum of hypertrophic cardiomyopathy.
      Clinically, HCM is usually recognized by maximal LV wall thickness ≥15 mm, with wall thickness of 13 to 14 mm considered borderline, particularly in the presence of other compelling information (eg, family history of HCM), based on echocardiography. In terms of LV wall-thickness measurements, the literature at this time has been largely focused on echocardiography, although cardiovascular magnetic resonance (CMR) is now used with increasing frequency in HCM,
      • Maron M.S.
      • Maron B.J.
      • Harrigan C.
      • et al.
      Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance.
      and we presume that data with this latter modality will increasingly emerge. In the case of children, increased LV wall thickness is defined as wall thickness ≥2 standard deviations above the mean (z score ≥2) for age, sex, or body size. However, it should be underscored that in principle, any degree of wall thickness is compatible with the presence of the HCM genetic substrate and that an emerging subgroup within the broad clinical spectrum is composed of family members with disease-causing sarcomere mutations but without evidence of the disease phenotype (ie, LV hypertrophy).
      • Christiaans I.
      • Lekanne dit Deprez R.H.
      • van Langen I.M.
      • et al.
      Ventricular fibrillation in MYH7-related hypertrophic cardiomyopathy before onset of ventricular hypertrophy.
      • Ho C.Y.
      • Sweitzer N.K.
      • McDonough B.
      • et al.
      Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy.
      • Ho C.Y.
      • Lopez B.
      • Coelho-Filho O.R.
      • et al.
      Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy.
      • Nagueh S.F.
      • McFalls J.
      • Meyer D.
      • et al.
      Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease.
      These individuals are usually referred to as being “genotype positive/phenotype negative” or as having “subclinical HCM.” Furthermore, although a myriad of patterns and distribution of LV hypertrophy (including diffuse and marked) have been reported in HCM,
      • Maron M.S.
      • Maron B.J.
      • Harrigan C.
      • et al.
      Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance.
      • Klues H.G.
      • Schiffers A.
      • Maron B.J.
      Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients.
      • Maron B.J.
      • Gottdiener J.S.
      • Epstein S.E.
      Patterns and significance of distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy: a wide angle, two dimensional echocardiographic study of 125 patients.
      about one third of patients have largely segmental wall thickening involving only a small portion of the left ventricle, and indeed such patients with HCM usually have normal calculated LV mass.
      • Maron M.S.
      • Maron B.J.
      • Harrigan C.
      • et al.
      Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance.
      The clinical diagnosis of HCM may also be buttressed by other typical features, such as family history of the disease, cardiac symptoms, tachyarrhythmias, or electrocardiographic abnormalities.
      • Maron B.J.
      Hypertrophic cardiomyopathy: a systematic review.
      • Maron B.J.
      • McKenna W.J.
      • Danielson G.K.
      • et al.
      American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy.
      Differential diagnosis of HCM and other cardiac conditions (with LV hypertrophy) may arise, most commonly with hypertensive heart disease and the physiologic remodeling associated with athletic training (“athlete’s heart”).
      • Maron B.J.
      • Pelliccia A.
      • Spirito P.
      Cardiac disease in young trained athletes: insights into methods for distinguishing athlete’s heart from structural heart disease, with particular emphasis on hypertrophic cardiomyopathy.
      • Maron B.J.
      • Pelliccia A.
      The heart of trained athletes: cardiac remodeling and the risks of sports, including sudden death.
      • Maron B.J.
      Distinguishing hypertrophic cardiomyopathy from athlete’s heart physiological remodelling: clinical significance, diagnostic strategies and implications for preparticipation screening.
      • Pelliccia A.
      • Kinoshita N.
      • Pisicchio C.
      • et al.
      Long-term clinical consequences of intense, uninterrupted endurance training in Olympic athletes.
      • Pelliccia A.
      • Di Paolo F.M.
      • De Blasiis E.
      • et al.
      Prevalence and clinical significance of aortic root dilation in highly trained competitive athletes.
      These are not uncommon clinical scenarios, and confusion between mild morphologic expressions of HCM and other conditions with LV hypertrophy usually arises when maximum wall thickness is in the modest range of 13 to 15 mm. In older patients with LV hypertrophy and a history of systemic hypertension, coexistence of HCM is often a consideration. The likelihood of HCM can be determined by identification of a diagnostic sarcomere mutation or inferred by marked LV thickness >25 mm and/or LVOT obstruction with systolic anterior motion (SAM) and mitral-septal contact.
      The important distinction between pathologic LV hypertrophy (ie, HCM) and physiologic LV hypertrophy (ie, athlete’s heart) is impacted by the recognition that athletic conditioning can produce LV, right ventricular, and left atrial (LA) chamber enlargement, ventricular septal thickening, and even aortic enlargement
      • Pelliccia A.
      • Di Paolo F.M.
      • De Blasiis E.
      • et al.
      Prevalence and clinical significance of aortic root dilation in highly trained competitive athletes.
      but is often resolved by noninvasive markers, including sarcomeric mutations or family history of HCM, LV cavity dimension (if enlarged, favoring athlete’s heart), diastolic function, pattern of LV hypertrophy (if unusual location or noncontiguous, favoring HCM), or short deconditioning periods in which a decrease in wall thickness would favor athlete’s heart.
      • Maron B.J.
      • Pelliccia A.
      • Spirito P.
      Cardiac disease in young trained athletes: insights into methods for distinguishing athlete’s heart from structural heart disease, with particular emphasis on hypertrophic cardiomyopathy.
      • Maron B.J.
      • Pelliccia A.
      The heart of trained athletes: cardiac remodeling and the risks of sports, including sudden death.
      • Maron B.J.
      Distinguishing hypertrophic cardiomyopathy from athlete’s heart physiological remodelling: clinical significance, diagnostic strategies and implications for preparticipation screening.
      • Pelliccia A.
      • Kinoshita N.
      • Pisicchio C.
      • et al.
      Long-term clinical consequences of intense, uninterrupted endurance training in Olympic athletes.
      • Pelliccia A.
      • Di Paolo F.M.
      • De Blasiis E.
      • et al.
      Prevalence and clinical significance of aortic root dilation in highly trained competitive athletes.
      Notably, it is evident that metabolic or infiltrative storage disorders with LV hypertrophy in babies, older children, and young adults can mimic clinically diagnosed HCM (attributable to sarcomeric protein mutations), for example, conditions such as mitochondrial disease,
      • Cox G.F.
      • Sleeper L.A.
      • Lowe A.M.
      • et al.
      Factors associated with establishing a causal diagnosis for children with cardiomyopathy.
      • Scaglia F.
      • Towbin J.A.
      • Craigen W.J.
      • et al.
      Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease.
      Fabry disease,
      • Monserrat L.
      • Gimeno-Blanes J.R.
      • Marin F.
      • et al.
      Prevalence of Fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy.
      or storage diseases caused by mutations in the genes encoding the γ-2-regulatory subunit of the adenosine monophosphate (AMP)-activated protein kinase (PRKAG2) or the X-linked lysosome-associated membrane protein gene (LAMP2; Danon disease).
      • Alcalai R.
      • Seidman J.G.
      • Seidman C.E.
      Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics.
      • Arad M.
      • Maron B.J.
      • Gorham J.M.
      • et al.
      Glycogen storage diseases presenting as hypertrophic cardiomyopathy.
      • Maron B.J.
      • Roberts W.C.
      • Arad M.
      • et al.
      Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy.
      • Yang Z.
      • McMahon C.J.
      • Smith L.R.
      • et al.
      Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children.
      Use of the term HCM is not appropriate to describe these and other patients with LV hypertrophy that occurs in the context of a multisystem disorder such as Noonan syndrome (with craniofacial and congenital heart malformations, as well as LV hypertrophy from mutations in genes of the RAS [RAt Sarcoma] pathway
      • Maron B.J.
      • Semsarian C.
      Emergence of gene mutation carriers and the expanding disease spectrum of hypertrophic cardiomyopathy.
      • Maron M.S.
      • Maron B.J.
      • Harrigan C.
      • et al.
      Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance.
      ), or distinct cardiomyopathies such as Pompe disease (also a glycogen storage disease II, with skeletal muscle weakness and cardiomyopathy because of deficiency of α1,4 glycosidase [acid maltase])
      • Colan S.D.
      • Lipshultz S.E.
      • Lowe A.M.
      • et al.
      Epidemiology and cause-specific outcome of hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry.
      • Gelb B.D.
      • Tartaglia M.
      Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction.
      • Montalvo A.L.
      • Bembi B.
      • Donnarumma M.
      • et al.
      Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II.
      • Pandit B.
      • Sarkozy A.
      • Pennacchio L.A.
      • et al.
      Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.
      • van den Hout H.M.
      • Hop W.
      • van Diggelen O.P.
      • et al.
      The natural course of infantile Pompe’s disease: 20 original cases compared with 133 cases from the literature.
      (Figure 1). In addition, differential diagnosis of HCM may require distinction from systemic hypertension or physiologic athlete’s heart
      • Maron B.J.
      • Pelliccia A.
      The heart of trained athletes: cardiac remodeling and the risks of sports, including sudden death.
      or from dilated cardiomyopathy when HCM presents in the end stage.
      • Harris K.M.
      • Spirito P.
      • Maron M.S.
      • et al.
      Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy.
      Figure thumbnail gr1
      Figure 1Summary of the nomenclature that distinguishes HCM from other genetic diseases associated with LV hypertrophy. ∗At this time the overwhelming evidence links the clinical diagnosis of HCM with a variety of genes encoding protein components of the cardiac sarcomere. However, it is possible that in the future other nonsarcomeric (but also nonmetabolic) genes may prove to cause HCM. †An example is Noonan syndrome with cardiomyopathy.
      Modified with permission from Maron et al.
      • Maron B.J.
      • Seidman C.E.
      • Ackerman M.J.
      • et al.
      How should hypertrophic cardiomyopathy be classified? What’s in a name? Dilemmas in nomenclature characterizing hypertrophic cardiomyopathy and left ventricular hypertrophy.

      2.2.3 Impact of Genetics

      On the basis of the genotype-phenotype data available at this time, HCM is regarded here as a disease entity caused by autosomal dominant mutations in genes encoding protein components of the sarcomere and its constituent myofilament elements.
      • Alcalai R.
      • Seidman J.G.
      • Seidman C.E.
      Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics.
      • Ahmad F.
      • Seidman J.G.
      • Seidman C.E.
      The genetic basis for cardiac remodeling.
      • Bos J.M.
      • Towbin J.A.
      • Ackerman M.J.
      Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy.
      • Seidman J.G.
      • Seidman C.
      The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms.
      Intergenetic diversity is compounded by considerable intragene heterogeneity, with >1400 mutations identified among at least 8 genes. The current weight of evidence supports the view that the vast majority of genes and mutations responsible for clinically diagnosed HCM encode proteins within and associated with the sarcomere, accounting in large measure for those patients described in the voluminous amount of HCM literature published over 50 years.
      • Alcalai R.
      • Seidman J.G.
      • Seidman C.E.
      Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics.
      • Ahmad F.
      • Seidman J.G.
      • Seidman C.E.
      The genetic basis for cardiac remodeling.
      • Bos J.M.
      • Towbin J.A.
      • Ackerman M.J.
      Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy.
      • Seidman J.G.
      • Seidman C.
      The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms.
      In conclusion, the writing committee believes that the most prudent recommendation for nomenclature is that hypertrophic cardiomyopathy and the acronym HCM remain a clinical diagnosis limited to those patients in whom (1) overt disease expression (with LV hypertrophy) appears to be confined to the heart and (2) the definitive mutation is either one of a gene encoding proteins of the cardiac sarcomere or alternatively when the genotype is unresolved using current genetic testing. Therefore, nomenclature that describes patients as “Noonan hypertrophic cardiomyopathy” is discouraged, whereas “Noonan syndrome with LV hypertrophy” or “Noonan syndrome with cardiomyopathy” is preferred.

      2.2.4 Hypertrophic Cardiomyopathy Centers

      The writing committee considers it important to emphasize that HCM is a complex disease entity with a broad (and increasing) clinical and genetic spectrum.
      • Maron B.J.
      Hypertrophic cardiomyopathy: a systematic review.
      Although HCM is one of the most common forms of genetic heart disease and relatively common in the general population,
      • Maron B.J.
      • Gardin J.M.
      • Flack J.M.
      • et al.
      Prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiographic analysis of 4111 subjects in the CARDIA Study Coronary Artery Risk Development in (Young) Adults.
      this disease entity is infrequent in general clinical practice, with most cardiologists responsible for the care of only a few patients with HCM.
      • Maron B.J.
      Hypertrophic cardiomyopathy centers.
      This principle has led to an impetus for establishing clinical programs of excellence—usually within established centers—in which cardiovascular care is focused on the management of HCM (ie, “HCM centers”).
      • Maron B.J.
      Hypertrophic cardiomyopathy centers.
      • Ingles J.
      • Lind J.M.
      • Phongsavan P.
      • et al.
      Psychosocial impact of specialized cardiac genetic clinics for hypertrophic cardiomyopathy.
      Such programs are stfned by cardiologists and cardiac surgeons familiar with the contemporary management of HCM and offer all diagnostic and treatment options, including genetic testing and counseling, comprehensive transthoracic echocardiogram (TTE), CMR imaging, both surgical septal myectomy and alcohol ablation, and the management of atrial fibrillation (AF)/atrial flutter, and ICDs. Another advantage is the potential to perform outcomes research on large groups of patients. Although the writing committee does not necessarily recommend that all patients with HCM should be evaluated in such centers, nevertheless, it is the strong view that patients with this disease may well benefit from a clinical environment with specific expertise in HCM. The selection of patients for referral to an HCM center should be based largely on the judgment of the managing cardiologist and the degree to which he or she is comfortable advising and evaluating patients with HCM with a particular clinical profile.

      3. Clinical Course and Natural History, Including Absence of Complications

      HCM is a heterogeneous cardiac disease with a diverse clinical presentation and course, presenting in all age groups from infancy to the very elderly.
      • Maron B.J.
      Hypertrophic cardiomyopathy: a systematic review.
      • Maron B.J.
      • McKenna W.J.
      • Danielson G.K.
      • et al.
      American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy.
      • Harris K.M.
      • Spirito P.
      • Maron M.S.
      • et al.
      Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy.
      • Maron M.S.
      • Olivotto I.
      • Betocchi S.
      • et al.
      Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy.
      Most fnected individuals probably achieve a normal life expectancy without disability or the necessity for major therapeutic interventions.
      • Cannan C.R.
      • Reeder G.S.
      • Bailey K.R.
      • et al.
      Natural history of hypertrophic cardiomyopathy: a population-based study, 1976 through 1990.
      • Cecchi F.
      • Olivotto I.
      • Montereggi A.
      • et al.
      Hypertrophic cardiomyopathy in Tuscany: clinical course and outcome in an unselected regional population.
      • Maron B.J.
      • Casey S.A.
      • Poliac L.C.
      • et al.
      Clinical course of hypertrophic cardiomyopathy in a regional United States cohort.
      • Spirito P.
      • Chiarella F.
      • Carratino L.
      • et al.
      Clinical course and prognosis of hypertrophic cardiomyopathy in an outpatient population.
      On the other hand, in some patients, HCM is associated with disease complications that may be profound, with the potential to result in disease progression or premature death.
      • Maron B.J.
      Hypertrophic cardiomyopathy: a systematic review.
      • Maron B.J.
      • McKenna W.J.
      • Danielson G.K.
      • et al.
      American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy.
      • Harris K.M.
      • Spirito P.
      • Maron M.S.
      • et al.
      Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy.
      • Maron M.S.
      • Olivotto I.
      • Betocchi S.
      • et al.
      Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy.
      • Elliott P.M.
      • Poloniecki J.
      • Dickie S.
      • et al.
      Sudden death in hypertrophic cardiomyopathy: identification of high risk patients.
      • Elliott P.M.
      • Gimeno Blanes J.R.
      • Mahon N.G.
      • et al.
      Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy.
      When the disease does result in significant complications, there are 3 relatively discrete but not mutually exclusive pathways of clinical progression (Figure 2):
      • 1.
        SCD due to unpredictable ventricular tachyarrhythmias, most commonly in young asymptomatic patients <35 years of age
        • Elliott P.M.
        • Poloniecki J.
        • Dickie S.
        • et al.
        Sudden death in hypertrophic cardiomyopathy: identification of high risk patients.
        • Elliott P.M.
        • Gimeno Blanes J.R.
        • Mahon N.G.
        • et al.
        Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy.
        • Maron B.J.
        • Semsarian C.
        • Shen W.K.
        • et al.
        Circadian patterns in the occurrence of malignant ventricular tachyarrhythmias triggering defibrillator interventions in patients with hypertrophic cardiomyopathy.
        • Maron B.J.
        Contemporary insights and strategies for risk stratification and prevention of sudden death in hypertrophic cardiomyopathy.
        • Maron B.J.
        • Shen W.K.
        • Link M.S.
        • et al.
        Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy.
        • Maron B.J.
        • Spirito P.
        • Shen W.K.
        • et al.
        Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy.
        • Maron B.J.
        • Spirito P.
        Implantable defibrillators and prevention of sudden death in hypertrophic cardiomyopathy.
        • Maron B.J.
        • Olivotto I.
        • Spirito P.
        • et al.
        Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral-based patient population.
        • Maron B.J.
        Sudden death in young athletes.
        • Maron B.J.
        • Doerer J.J.
        • Haas T.S.
        • et al.
        Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006.
        (including competitive athletes).
        • Maron B.J.
        Sudden death in young athletes.
        • Maron B.J.
        • Doerer J.J.
        • Haas T.S.
        • et al.
        Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006.
      • 2.
        Heart failure characterized by exertional dyspnea (with or without chest pain) that may be progressive despite preserved systolic function and sinus rhythm, or in a small proportion of patients, heart failure may progress to the end stage with LV remodeling and systolic dysfunction caused by extensive myocardial scarring.
        • Harris K.M.
        • Spirito P.
        • Maron M.S.
        • et al.
        Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy.
      • 3.
        AF, either paroxysmal or chronic, also associated with various degrees of heart failure
        • Olivotto I.
        • Cecchi F.
        • Casey S.A.
        • et al.
        Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy.
        and an increased risk of systemic thromboembolism and both fatal and nonfatal stroke.
      Figure thumbnail gr2
      Figure 2Prognosis profiles for HCM and targets for therapy. AF indicates atrial fibrillation.
      Modified with permission from Maron et al.
      • Maron B.J.
      • McKenna W.J.
      • Danielson G.K.
      • et al.
      American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy.
      The natural history of HCM can be altered by a number of therapeutic interventions: ICDs for secondary or primary prevention of sudden death in patients with risk factors
      • Maron B.J.
      • Shen W.K.
      • Link M.S.
      • et al.
      Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy.
      • Maron B.J.
      • Spirito P.
      • Shen W.K.
      • et al.
      Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy.
      • Maron B.J.
      • Spirito P.
      Implantable defibrillators and prevention of sudden death in hypertrophic cardiomyopathy.
      ; drugs appropriate to control heart failure symptoms (principally those of exertional dyspnea and chest discomfort),
      • Maron B.J.
      Hypertrophic cardiomyopathy: a systematic review.
      • Maron B.J.
      • McKenna W.J.
      • Danielson G.K.
      • et al.
      American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy.
      surgical septal myectomy
      • Ommen S.R.
      • Maron B.J.
      • Olivotto I.
      • et al.
      Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy.
      or alcohol septal ablation
      • Sorajja P.
      • Valeti U.
      • Nishimura R.A.
      • et al.
      Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy.
      for progressive and drug-refractory heart failure caused by LVOT obstruction; heart transplantation for systolic (or less frequently intractable diastolic) dysfunction associated with severe unrelenting symptoms
      • Harris K.M.
      • Spirito P.
      • Maron M.S.
      • et al.
      Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy.
      ; and drug therapy or possibly radiofrequency ablation or surgical maze procedure for AF.
      • Bunch T.J.
      • Munger T.M.
      • Friedman P.A.
      • et al.
      Substrate and procedural predictors of outcomes after catheter ablation for atrial fibrillation in patients with hypertrophic cardiomyopathy.
      • Gaita F.
      • Di Donna P.
      • Olivotto I.
      • et al.
      Usefulness and safety of transcatheter ablation of atrial fibrillation in patients with hypertrophic cardiomyopathy.
      • Kilicaslan F.
      • Verma A.
      • Saad E.
      • et al.
      Efficacy of catheter ablation of atrial fibrillation in patients with hypertrophic obstructive cardiomyopathy.

      4. Pathophysiology

      The pathophysiology of HCM is complex and consists of multiple interrelated abnormalities, including LVOT obstruction, diastolic dysfunction, mitral regurgitation, myocardial ischemia, and arrhythmias.
      • Maron B.J.
      Hypertrophic cardiomyopathy: a systematic review.
      • Wigle E.D.
      • Sasson Z.
      • Henderson M.A.
      • et al.
      Hypertrophic cardiomyopathy: the importance of the site and the extent of hypertrophy: a review.
      • Wigle E.D.
      • Rakowski H.
      • Kimball B.P.
      • et al.
      Hypertrophic cardiomyopathy: clinical spectrum and treatment.
      It is clinically important to distinguish between the obstructive and nonobstructive forms of HCM because management strategies are largely dependent on the presence or absence of symptoms caused by obstruction.

      4.1 LVOT Obstruction

      The original observations by Brock
      • Brock R.
      Functional obstruction of the left ventricle: acquired aortic subvalvar stenosis.
      and Braunwald et al
      • Braunwald E.
      • Lambert C.T.
      • Rockoff S.D.
      • et al.
      Idiopathic hypertrophic subaortic stenosis, I: a description of the disease based upon an analysis of 64 patients.
      emphasized the functional subvalvular LVOT gradient, which was highly influenced by alterations in the load and contractility of the left ventricle. The clinical significance of the outflow tract gradient has periodically been controversial,
      • Criley J.M.
      • Siegel R.J.
      Has “obstruction” hindered our understanding of hypertrophic cardiomyopathy?.
      • Criley J.M.
      • Siegel R.J.
      Obstruction is unimportant in the pathophysiology of hypertrophic cardiomyopathy.
      • Criley J.M.
      Unobstructed thinking (and terminology) is called for in the understanding and management of hypertrophic cardiomyopathy.
      • Maron B.J.
      • Maron M.S.
      • Wigle E.D.
      • et al.
      The 50-year history, controversy, and clinical implications of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy: from idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy.
      but careful studies have shown definitively that true mechanical obstruction to outflow does occur.
      • Wigle E.D.
      • Sasson Z.
      • Henderson M.A.
      • et al.
      Hypertrophic cardiomyopathy: the importance of the site and the extent of hypertrophy: a review.
      • Wigle E.D.
      • Rakowski H.
      • Kimball B.P.
      • et al.
      Hypertrophic cardiomyopathy: clinical spectrum and treatment.
      For HCM, it is the peak instantaneous LV outflow gradient rather than the mean gradient that influences treatment decisions. Throughout the remainder of this document the term gradient will be used to denote peak instantaneous gradient. Up to one third of patients with HCM will have obstruction under basal (resting) conditions (defined as gradients ≥30 mm Hg). Another one third or more of patients will have labile, physiologically provoked gradients (<30 mm Hg at rest and ≥30 mm Hg with physiologic provocation).
      • Maron M.S.
      • Olivotto I.
      • Zenovich A.G.
      • et al.
      Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction.
      The final one third of patients will have the nonobstructive form of HCM (gradients <30 mm Hg at rest and with provocation) (Table 2). Marked gradients ≥50 mm Hg, either at rest or with provocation, represent the conventional threshold for surgical or percutaneous intervention if symptoms cannot be controlled with medications.
      Table 2Definitions of dynamic left ventricular outflow tract obstruction
      Hemodynamic stateConditionsOutflow gradient
      Either the peak instantaneous continuous wave Doppler gradient or the peak-to-peak cardiac catheterization gradient, which are equivalent in hypertrophic cardiomyopathy.73,74
      Basal obstructionRest≥30 mm Hg
      Gradients ≥50 mm Hg either at rest or with provocation are considered the threshold for septal reduction therapy in severely symptomatic patients.
      NonobstructiveRest<30 mm Hg
      Physiologically provoked<30 mm Hg
      Labile obstructionRest<30 mm Hg
      Gradients ≥50 mm Hg either at rest or with provocation are considered the threshold for septal reduction therapy in severely symptomatic patients.
      Physiologically provoked≥30 mm Hg
      Gradients ≥50 mm Hg either at rest or with provocation are considered the threshold for septal reduction therapy in severely symptomatic patients.
      Either the peak instantaneous continuous wave Doppler gradient or the peak-to-peak cardiac catheterization gradient, which are equivalent in hypertrophic cardiomyopathy.
      • Panza J.A.
      • Petrone R.K.
      • Fananapazir L.
      • et al.
      Utility of continuous wave Doppler echocardiography in the noninvasive assessment of left ventricular outflow tract pressure gradient in patients with hypertrophic cardiomyopathy.
      • Sasson Z.
      • Yock P.G.
      • Hatle L.K.
      • et al.
      Doppler echocardiographic determination of the pressure gradient in hypertrophic cardiomyopathy.
      Gradients ≥50 mm Hg either at rest or with provocation are considered the threshold for septal reduction therapy in severely symptomatic patients.
      Obstruction causes an increase in LV systolic pressure, which leads to a complex interplay of abnormalities including prolongation of ventricular relaxation, elevation of LV diastolic pressure, mitral regurgitation, myocardial ischemia, and a decrease in forward cardiac output.
      • Maron B.J.
      Hypertrophic cardiomyopathy: a systematic review.
      • Wigle E.D.
      • Sasson Z.
      • Henderson M.A.
      • et al.
      Hypertrophic cardiomyopathy: the importance of the site and the extent of hypertrophy: a review.
      • Wigle E.D.
      • Rakowski H.
      • Kimball B.P.
      • et al.
      Hypertrophic cardiomyopathy: clinical spectrum and treatment.
      Outflow obstruction usually occurs in HCM by virtue of mitral valve SAM and mitral-septal contact. Although the mechanism of the outflow tract gradient in HCM was initially thought to be caused by systolic contraction of the hypertrophied basal ventricular septum encroaching on the LVOT, most recent studies emphasize that during ventricular systole, flow against the abnormally positioned mitral valve apparatus results in drag force on a portion of the mitral valve leaflets, which pushes the leaflets into the outflow tract.
      • Wigle E.D.
      • Sasson Z.
      • Henderson M.A.
      • et al.
      Hypertrophic cardiomyopathy: the importance of the site and the extent of hypertrophy: a review.
      • Wigle E.D.
      • Rakowski H.
      • Kimball B.P.
      • et al.
      Hypertrophic cardiomyopathy: clinical spectrum and treatment.
      • Shah P.M.
      • Taylor R.D.
      • Wong M.
      Abnormal mitral valve coaptation in hypertrophic obstructive cardiomyopathy: proposed role in systolic anterior motion of mitral valve.
      • Sherrid M.V.
      • Chu C.K.
      • Delia E.
      • et al.
      An echocardiographic study of the fluid mechanics of obstruction in hypertrophic cardiomyopathy.
      • Sherrid M.V.
      Dynamic left ventricular outflow obstruction in hypertrophic cardiomyopathy revisited: significance, pathogenesis, and treatment.
      • Sherrid M.V.
      • Gunsburg D.Z.
      • Moldenhauer S.
      • et al.
      Systolic anterior motion begins at low left ventricular outflow tract velocity in obstructive hypertrophic cardiomyopathy.
      Muscular obstruction can also be present in the midcavitary region, occasionally because of hypertrophied papillary muscles abutting the septum
      • Falicov R.E.
      • Resnekov L.
      • Bharati S.
      • et al.
      Mid-ventricular obstruction: a variant of obstructive cardiomyopathy.
      or anomalous papillary muscle insertion into the anterior mitral leaflet.
      • Maron B.J.
      • Nishimura R.A.
      • Danielson G.K.
      Pitfalls in clinical recognition and a novel operative approach for hypertrophic cardiomyopathy with severe outflow obstruction due to anomalous papillary muscle.
      Obstruction to LV outflow is dynamic, varying with loading conditions and contractility of the ventricle.
      • Braunwald E.
      • Lambert C.T.
      • Rockoff S.D.
      • et al.
      Idiopathic hypertrophic subaortic stenosis, I: a description of the disease based upon an analysis of 64 patients.
      Increased myocardial contractility, decreased ventricular volume, or decreased afterload increases the degree of subaortic obstruction. Patients may have little or no obstruction of the LVOT at rest but can generate large LVOT gradients under conditions such as exercise, the strain phase of the Valsalva maneuver, or during pharmacologic provocation.
      • Wigle E.D.
      • Sasson Z.
      • Henderson M.A.
      • et al.
      Hypertrophic cardiomyopathy: the importance of the site and the extent of hypertrophy: a review.
      • Wigle E.D.
      • Rakowski H.
      • Kimball B.P.
      • et al.
      Hypertrophic cardiomyopathy: clinical spectrum and treatment.
      There is often large spontaneous variation in the severity of the gradient during day-to-day activities or even with food or alcohol intake
      • Geske J.B.
      • Sorajja P.
      • Ommen S.R.
      • et al.
      Left ventricular outflow tract gradient variability in hypertrophic cardiomyopathy.
      ; exacerbation of symptoms during the postprandial period is common. Importantly, it has been well established that LVOT obstruction contributes to the debilitating heart failure–related symptoms that may occur in HCM
      • Wigle E.D.
      • Sasson Z.
      • Henderson M.A.
      • et al.
      Hypertrophic cardiomyopathy: the importance of the site and the extent of hypertrophy: a review.
      • Wigle E.D.
      • Rakowski H.
      • Kimball B.P.
      • et al.
      Hypertrophic cardiomyopathy: clinical spectrum and treatment.
      and is also a major determinant of outcome.
      • Maron M.S.
      • Olivotto I.
      • Betocchi S.
      • et al.
      Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy.
      The presence and magnitude of outflow obstruction are usually assessed with 2-dimensional echocardiography and continuous wave Doppler. It is a late-peaking systolic velocity that reflects the occurrence of subaortic obstruction late in systole, and the peak instantaneous gradient derived from the peak velocity should be reported. If the resting outflow gradient is <50 mm Hg, provocative measures may be used to ascertain if higher gradients can be elicited, preferably with physiologic exercise (stress echocardiography) but alternatively with the Valsalva maneuver or selectively with amyl nitrite.
      • Braunwald E.
      • Lambert C.T.
      • Rockoff S.D.
      • et al.
      Idiopathic hypertrophic subaortic stenosis, I: a description of the disease based upon an analysis of 64 patients.
      • Maron B.J.
      • McKenna W.J.
      • Danielson G.K.
      • et al.
      American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy.
      Provocation with dobutamine infusion during Doppler echocardiography is no longer recommended as a strategy to induce outflow gradients in HCM. However in equivocal cases, cardiac catheterization with isoproterenol infusion may further aid in eliciting a provocable gradient.
      • Elesber A.
      • Nishimura R.A.
      • Rihal C.S.
      • et al.
      Utility of isoproterenol to provoke outflow tract gradients in patients with hypertrophic cardiomyopathy.
      Otherwise, routine invasive cardiac catheterization to document outflow gradients is necessary only when there are discordant data from Doppler echocardiography and the physical examination.
      • Maron B.J.
      • McKenna W.J.
      • Danielson G.K.
      • et al.
      American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy.
      The peak-to-peak gradient obtained with catheterization most closely approximates the peak instantaneous gradient by continuous wave Doppler echocardiography.
      • Panza J.A.
      • Petrone R.K.
      • Fananapazir L.
      • et al.
      Utility of continuous wave Doppler echocardiography in the noninvasive assessment of left ventricular outflow tract pressure gradient in patients with hypertrophic cardiomyopathy.
      • Sasson Z.
      • Yock P.G.
      • Hatle L.K.
      • et al.
      Doppler echocardiographic determination of the pressure gradient in hypertrophic cardiomyopathy.

      4.2 Diastolic Dysfunction

      Diastolic dysfunction arising from multiple factors is a major pathophysiologic abnormality in HCM that ultimately fnects both ventricular relaxation and chamber stiffness.
      • Wigle E.D.
      • Sasson Z.
      • Henderson M.A.
      • et al.
      Hypertrophic cardiomyopathy: the importance of the site and the extent of hypertrophy: a review.
      • Wigle E.D.
      • Rakowski H.
      • Kimball B.P.
      • et al.
      Hypertrophic cardiomyopathy: clinical spectrum and treatment.
      • Paulus W.J.
      • Lorell B.H.
      • Craig W.E.
      • et al.
      Comparison of the effects of nitroprusside and nifedipine on diastolic properties in patients with hypertrophic cardiomyopathy: altered left ventricular loading or improved muscle inactivation?.
      Impairment of ventricular relaxation results from the systolic contraction load caused by outflow tract obstruction, nonuniformity of ventricular contraction and relaxation, and delayed inactivation caused by abnormal intracellular calcium reuptake. Severe hypertrophy of the myocardium results in an increase in chamber stiffness. Diffuse myocardial ischemia may further fnect both relaxation and chamber stiffness. A compensatory increase in the contribution of late diastolic filling during atrial systole is associated with these alterations.
      • Bonow R.O.
      • Dilsizian V.
      • Rosing D.R.
      • et al.
      Verapamil-induced improvement in left ventricular diastolic filling and increased exercise tolerance in patients with hypertrophic cardiomyopathy: short- and long-term effects.
      With exercise or any other type of catecholamine stimulation, the decrease in diastolic filling period as well as myocardial ischemia will further lead to severe abnormalities of diastolic filling of the heart, with chest pain and/or an increase in pulmonary venous pressure causing dyspnea.

      4.3 Myocardial Ischemia

      Severe myocardial ischemia and even infarction may occur in HCM.
      • Cannon III, R.O.
      • Rosing D.R.
      • Maron B.J.
      • et al.
      Myocardial ischemia in patients with hypertrophic cardiomyopathy: contribution of inadequate vasodilator reserve and elevated left ventricular filling pressures.
      • Maron M.S.
      • Olivotto I.
      • Maron B.J.
      • et al.
      The case for myocardial ischemia in hypertrophic cardiomyopathy.
      The myocardial ischemia is frequently unrelated to the atherosclerotic epicardial coronary artery disease (CAD) but is caused by supply–demand mismatch. Patients with HCM of any age have increased oxygen demand caused by the hypertrophy and adverse loading conditions. They also have compromised coronary blood flow to the LV myocardium because of intramural arterioles with thickened walls attributable to medial hypertrophy associated with luminal narrowing.
      • Maron B.J.
      • Wolfson J.K.
      • Epstein S.E.
      • et al.
      Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy.

      4.4 Autonomic Dysfunction

      During exercise, approximately 25% of patients with HCM have an abnormal blood pressure response defined by either a failure of systolic blood pressure to rise >20 mm Hg or a fall in systolic blood pressure.
      • Frenneaux M.P.
      • Counihan P.J.
      • Caforio A.L.
      • et al.
      Abnormal blood pressure response during exercise in hypertrophic cardiomyopathy.
      • Sadoul N.
      • Prasad K.
      • Elliott P.M.
      • et al.
      Prospective prognostic assessment of blood pressure response during exercise in patients with hypertrophic cardiomyopathy.
      The presence of this finding is associated with a poorer prognosis.
      • Sadoul N.
      • Prasad K.
      • Elliott P.M.
      • et al.
      Prospective prognostic assessment of blood pressure response during exercise in patients with hypertrophic cardiomyopathy.
      • Olivotto I.
      • Maron B.J.
      • Montereggi A.
      • et al.
      Prognostic value of systemic blood pressure response during exercise in a community-based patient population with hypertrophic cardiomyopathy.
      This inability to augment and sustain systolic blood pressure during exercise is caused by either the dynamic LVOT obstruction or systemic vasodilatation during exercise. It is speculated that autonomic dysregulation
      • Frenneaux M.P.
      • Counihan P.J.
      • Caforio A.L.
      • et al.
      Abnormal blood pressure response during exercise in hypertrophic cardiomyopathy.
      is present in patients with HCM and that the fall in blood pressure associated with bradycardia may be an abnormal reflex response to obstruction.

      4.5 Mitral Regurgitation

      Mitral regurgitation is common in patients with LVOT obstruction and may play a primary role in producing symptoms of dyspnea. The temporal sequence of events of eject-obstruct-leak supports the concept that the mitral regurgitation in most patients is a secondary phenomenon.
      • Wigle E.D.
      • Sasson Z.
      • Henderson M.A.
      • et al.
      Hypertrophic cardiomyopathy: the importance of the site and the extent of hypertrophy: a review.
      • Wigle E.D.
      • Rakowski H.
      • Kimball B.P.
      • et al.
      Hypertrophic cardiomyopathy: clinical spectrum and treatment.
      • Wigle E.D.
      • Adelman A.G.
      • Auger P.
      • et al.
      Mitral regurgitation in muscular subaortic stenosis.
      The mitral regurgitation is usually caused by the distortion of the mitral valve apparatus from the SAM secondary to the LVOT obstruction. The jet of mitral regurgitation is directed laterally and posteriorly and predominates during mid and late systole. An anteriorly directed jet should suggest an intrinsic abnormality of the mitral valve. If the mitral regurgitation is caused by distortion of leaflet motion by SAM of the mitral valve, the severity of the mitral regurgitation may be proportional to the LVOT obstruction in some patients. Changes in ventricular load and contractility that fnect the severity of outflow tract obstruction similarly fnect the degree of mitral regurgitation. It is important to identify patients with additional intrinsic disease of the mitral valve apparatus (prolapse or flail), because this finding influences subsequent treatment options.
      • Zhu W.X.
      • Oh J.K.
      • Kopecky S.L.
      • et al.
      Mitral regurgitation due to ruptured chordae tendineae in patients with hypertrophic obstructive cardiomyopathy.

      5. Diagnosis

      The clinical diagnosis of HCM is conventionally made with cardiac imaging, at present most commonly with 2-dimensional echocardiography and increasingly with CMR. Morphologic diagnosis is based on the presence of a hypertrophied and nondilated left ventricle in the absence of another cardiac or systemic disease capable of producing the magnitude of hypertrophy evident in a patient (usually ≥15 mm in adults or the equivalent relative to body surface area in children). Genetic testing, which is now commercially available, is a powerful strategy for definitive diagnosis of fnected genetic status and is currently used most effectively in the identification of fnected relatives in families known to have HCM.

      5.1 Genetic Testing Strategies/Family Screening—Recommendations

      Class I
      • 1.
        Evaluation of familial inheritance and genetic counseling is recommended as part of the assessment of patients with HCM.
        • Ho C.Y.
        • Sweitzer N.K.
        • McDonough B.
        • et al.
        Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy.
        • Arad M.
        • Maron B.J.
        • Gorham J.M.
        • et al.
        Glycogen storage diseases presenting as hypertrophic cardiomyopathy.
        • Morita H.
        • Rehm H.L.
        • Menesses A.
        • et al.
        Shared genetic causes of cardiac hypertrophy in children and adults.
        • Niimura H.
        • Bachinski L.L.
        • Sangwatanaroj S.
        • et al.
        Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.
        • Van Driest S.L.
        • Ackerman M.J.
        • Ommen S.R.
        • et al.
        Prevalence and severity of “benign” mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy.
        • Van Driest S.L.
        • Jaeger M.A.
        • Ommen S.R.
        • et al.
        Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.
        (Level of Evidence: B)
      • 2.
        Patients who undergo genetic testing should also undergo counseling by someone knowledgeable in the genetics of cardiovascular disease so that results and their clinical significance can be appropriately reviewed with the patient.
        • Christiaans I.
        • van Langen I.M.
        • Birnie E.
        • et al.
        Genetic counseling and cardiac care in predictively tested hypertrophic cardiomyopathy mutation carriers: the patients’ perspective.
        • Michie S.
        • French D.
        • Allanson A.
        • et al.
        Information recall in genetic counselling: a pilot study of its assessment.
        • Michie S.
        • Allanson A.
        • Armstrong D.
        • et al.
        Objectives of genetic counselling: differing views of purchasers, providers and users.
        • Offit K.
        • Groeger E.
        • Turner S.
        • et al.
        The “duty to warn” a patient’s family members about hereditary disease risks.
        • Christiaans I.
        • van Langen I.M.
        • Birnie E.
        • et al.
        Quality of life and psychological distress in hypertrophic cardiomyopathy mutation carriers: a cross-sectional cohort study.
        (Level of Evidence: B)
      • 3.
        Screening (clinical, with or without genetic testing) is recommended in first-degree relatives of patients with HCM.
        • Ho C.Y.
        • Sweitzer N.K.
        • McDonough B.
        • et al.
        Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy.
        • Arad M.
        • Maron B.J.
        • Gorham J.M.
        • et al.
        Glycogen storage diseases presenting as hypertrophic cardiomyopathy.
        • Morita H.
        • Rehm H.L.
        • Menesses A.
        • et al.
        Shared genetic causes of cardiac hypertrophy in children and adults.
        • Niimura H.
        • Bachinski L.L.
        • Sangwatanaroj S.
        • et al.
        Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.
        • Van Driest S.L.
        • Jaeger M.A.
        • Ommen S.R.
        • et al.
        Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.
        • Fokstuen S.
        • Lyle R.
        • Munoz A.
        • et al.
        A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy.
        • Olivotto I.
        • Girolami F.
        • Ackerman M.J.
        • et al.
        Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy.
        (Level of Evidence: B)
      • 4.
        Genetic testing for HCM and other genetic causes of unexplained cardiac hypertrophy is recommended in patients with an atypical clinical presentation of HCM or when another genetic condition is suspected to be the cause.
        • Maron B.J.
        • Niimura H.
        • Casey S.A.
        • et al.
        Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations.
        • Rosenzweig A.
        • Watkins H.
        • Hwang D.S.
        • et al.
        Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes.
        • Spada M.
        • Pagliardini S.
        • Yasuda M.
        • et al.
        High incidence of later-onset Fabry disease revealed by newborn screening.
        (Level of Evidence: B)
      Class IIa
      • 1.
        Genetic testing is reasonable in the index patient to facilitate the identification of first-degree family members at risk for developing HCM.
        • Ho C.Y.
        • Sweitzer N.K.
        • McDonough B.
        • et al.
        Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy.
        • Van Driest S.L.
        • Ackerman M.J.
        • Ommen S.R.
        • et al.
        Prevalence and severity of “benign” mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy.
        • Fokstuen S.
        • Lyle R.
        • Munoz A.
        • et al.
        A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy.
        (Level of Evidence: B)
      Class IIb
      • 1.
        The usefulness of genetic testing in the assessment of risk of SCD in HCM is uncertain.
        • Moolman J.C.
        • Corfield V.A.
        • Posen B.
        • et al.
        Sudden death due to troponin T mutations.
        • Woo A.
        • Rakowski H.
        • Liew J.C.
        • et al.
        Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis.
        (Level of Evidence: B)
      Class III: No Benefit
      • 1.
        Genetic testing is not indicated in relatives when the index patient does not have a definitive pathogenic mutation.
        • Ho C.Y.
        • Sweitzer N.K.
        • McDonough B.
        • et al.
        Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy.
        • Arad M.
        • Maron B.J.
        • Gorham J.M.
        • et al.
        Glycogen storage diseases presenting as hypertrophic cardiomyopathy.
        • Morita H.
        • Rehm H.L.
        • Menesses A.
        • et al.
        Shared genetic causes of cardiac hypertrophy in children and adults.
        • Niimura H.
        • Bachinski L.L.
        • Sangwatanaroj S.
        • et al.
        Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.
        • Van Driest S.L.
        • Ackerman M.J.
        • Ommen S.R.
        • et al.
        Prevalence and severity of “benign” mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy.
        • Van Driest S.L.
        • Jaeger M.A.
        • Ommen S.R.
        • et al.
        Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.
        • Ho C.Y.
        • Lever H.M.
        • DeSanctis R.
        • et al.
        Homozygous mutation in cardiac troponin T: implications for hypertrophic cardiomyopathy.
        (Level of Evidence: B)
      • 2.
        Ongoing clinical screening is not indicated in genotype-negative relatives in families with HCM.
        • Ho C.Y.
        • Lever H.M.
        • DeSanctis R.
        • et al.
        Homozygous mutation in cardiac troponin T: implications for hypertrophic cardiomyopathy.
        • Ingles J.
        • Doolan A.
        • Chiu C.
        • et al.
        Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counseling.
        • Van Driest S.L.
        • Vasile V.C.
        • Ommen S.R.
        • et al.
        Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy.
        • Jeschke B.
        • Uhl K.
        • Weist B.
        • et al.
        A high risk phenotype of hypertrophic cardiomyopathy associated with a compound genotype of two mutated beta-myosin heavy chain genes.
        (Level of Evidence: B)
      See Online Data Supplement 1 for additional data regarding genetic testing strategies/family screening.
      HCM is caused by an autosomal dominant mutation in genes that encode sarcomere proteins or sarcomere-associated proteins. The most vigorous evidence indicates that 8 genes are known to definitively cause HCM: beta myosin heavy chain, myosin binding protein C, troponin T, troponin I, alpha tropomyosin, actin, regulatory light chain, and essential light chain.
      • Maron B.J.
      • Towbin J.A.
      • Thiene G.
      • et al.
      Contemporary definitions and classification of the cardiomyopathies: an American Heart Association scientific statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
      • Maron B.J.
      • Seidman C.E.
      • Ackerman M.J.
      • et al.
      How should hypertrophic cardiomyopathy be classified? What’s in a name? Dilemmas in nomenclature characterizing hypertrophic cardiomyopathy and left ventricular hypertrophy.
      • Alcalai R.
      • Seidman J.G.
      • Seidman C.E.
      Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics.
      • Ahmad F.
      • Seidman J.G.
      • Seidman C.E.
      The genetic basis for cardiac remodeling.
      • Bos J.M.
      • Towbin J.A.
      • Ackerman M.J.
      Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy.
      • Seidman J.G.
      • Seidman C.
      The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms.
      In addition, actinin and myozenin are associated with less definitive evidence for causing HCM. At this time there is inconclusive evidence to support other genes causing HCM,
      • Niimura H.
      • Bachinski L.L.
      • Sangwatanaroj S.
      • et al.
      Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.
      • Van Driest S.L.
      • Jaeger M.A.
      • Ommen S.R.
      • et al.
      Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.
      • Watkins H.
      • McKenna W.J.
      • Thierfelder L.
      • et al.
      Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.
      • Watkins H.
      • Rosenzweig A.
      • Hwang D.S.
      • et al.
      Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy.
      but research is ongoing and other genetic causes may be identified.
      • Morita H.
      • Rehm H.L.
      • Menesses A.
      • et al.
      Shared genetic causes of cardiac hypertrophy in children and adults.
      • Watkins H.
      • Thierfelder L.
      • Hwang D.S.
      • et al.
      Sporadic hypertrophic cardiomyopathy due to de novo myosin mutations.
      A single mutation in 1 of the 2 alleles (or copies) of a gene is sufficient to cause HCM; however, 5% of patients with HCM have ≥2 mutations in the same gene or different genes.
      • Ingles J.
      • Doolan A.
      • Chiu C.
      • et al.
      Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counseling.
      • Girolami F.
      • Ho C.Y.
      • Semsarian C.
      • et al.
      Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations.
      Genetic and/or clinical screening of all first-degree family members of patients with HCM is important to identify those with unrecognized disease. On the basis of family history, clinical screening, and pedigree analyses, the pattern of inheritance is ascertained to identify and counsel relatives at risk.
      • Christiaans I.
      • van Langen I.M.
      • Birnie E.
      • et al.
      Quality of life and psychological distress in hypertrophic cardiomyopathy mutation carriers: a cross-sectional cohort study.
      Because familial HCM is a dominant disorder, the risk that an fnected patient will transmit disease to each offspring is 50%. When a pathogenic mutation is identified in an index patient, the genetic status of each family member can be readily ascertained. Because HCM mutations are highly penetrant, a mutation conveys substantial (>95%) risk over a lifetime for developing clinical and/or phenotypic evidence of HCM.
      • Niimura H.
      • Bachinski L.L.
      • Sangwatanaroj S.
      • et al.
      Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.
      • Van Driest S.L.
      • Jaeger M.A.
      • Ommen S.R.
      • et al.
      Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.
      • Watkins H.
      • McKenna W.J.
      • Thierfelder L.
      • et al.
      Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.
      • Watkins H.
      • Rosenzweig A.
      • Hwang D.S.
      • et al.
      Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy.
      Genetic counseling before genetic testing will increase understanding of the medical and familial implications of test results, enabling informed decision making about potential risks and benefits.
      • Michie S.
      • French D.
      • Allanson A.
      • et al.
      Information recall in genetic counselling: a pilot study of its assessment.
      • Michie S.
      • Allanson A.
      • Armstrong D.
      • et al.
      Objectives of genetic counselling: differing views of purchasers, providers and users.
      Genetic counseling can also reduce potential psychologic responses to learning one’s mutation status.
      • Maron B.J.
      Hypertrophic cardiomyopathy: an important global disease.
      • Christiaans I.
      • van Langen I.M.
      • Birnie E.
      • et al.
      Quality of life and psychological distress in hypertrophic cardiomyopathy mutation carriers: a cross-sectional cohort study.
      Even when genetic testing is not undertaken, genetic counseling about the potential for familial transmission of HCM is medically important.
      The occurrence of HCM can be isolated or sporadic, but the frequency of sporadic HCM is unresolved. Sporadic HCM can reflect an inaccurate family history, incomplete penetrance (absence of clinical expression despite the presence of a mutation) in family members, or a de novo (new) mutation that can initiate new familial disease.
      • Morita H.
      • Rehm H.L.
      • Menesses A.
      • et al.
      Shared genetic causes of cardiac hypertrophy in children and adults.
      • Watkins H.
      • Thierfelder L.
      • Hwang D.S.
      • et al.
      Sporadic hypertrophic cardiomyopathy due to de novo myosin mutations.
      Because unrelated patients with HCM will have different mutations, a comprehensive sequence-based analysis of all HCM genes is necessary to define the pathogenic (eg, disease-causing) mutation in an index patient. Experienced clinical laboratories identify the pathogenic HCM mutation in approximately 60% to 70% of patients with a positive family history and approximately 10% to 50% of patients without a family history.
      • Morita H.
      • Rehm H.L.
      • Menesses A.
      • et al.
      Shared genetic causes of cardiac hypertrophy in children and adults.
      • Fokstuen S.
      • Lyle R.
      • Munoz A.
      • et al.
      A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy.
      Genetic testing may identify a pathogenic mutation (eg, analysis defines a sequence variant known to cause HCM) or a “likely pathogenic” mutation, a DNA variant that was previously unknown as a cause of HCM but has molecular characteristics that are similar to recognized HCM mutations. Genetic testing may also identify “variants of uncertain significance.” This term indicates that the nucleotide change is not commonly recognized to be variable (or polymorphic) in the general population and that some molecular characteristics of the variant suggest deleterious consequences (similar to all pathogenic mutations). Genetic analyses of family members can help establish or refute the causality of “likely pathogenic” and “variants of uncertain significance.” When a variant occurs in multiple clinically fnected family members but is absent from clinically unaffected adult family members, the likelihood for pathogenicity increases. In contrast, when a variant occurs in multiple clinically unaffected adult family members, the likelihood for pathogenicity is low.
      Adult patients with HCM and an established pathogenic mutation have increased risk for the combined endpoints of cardiovascular death, nonfatal stroke, or progression to New York Heart Association (NYHA) functional class III or IV compared with patients with HCM in whom no mutation is identified.
      • Olivotto I.
      • Girolami F.
      • Ackerman M.J.
      • et al.
      Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy.
      Studies suggest that the presence of >1 HCM-associated sarcomere mutation is associated with greater severity of disease.
      • Ingles J.
      • Doolan A.
      • Chiu C.
      • et al.
      Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counseling.
      • Van Driest S.L.
      • Vasile V.C.
      • Ommen S.R.
      • et al.
      Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy.
      • Saltzman A.J.
      • Mancini-DiNardo D.
      • Li C.
      • et al.
      The cardiac myosin binding protein C Arg502Trp mutation: a common cause of hypertrophic cardiomyopathy.
      • Kelly M.
      • Semsarian C.
      Multiple mutations in genetic cardiovascular disease: a marker of disease severity?.
      When genetic testing reveals a mutation in the index patient, ascertainment of genetic status in first-degree relatives can be predictive of risk for developing HCM.
      • Rosenzweig A.
      • Watkins H.
      • Hwang D.S.
      • et al.
      Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes.
      Genetic counseling should precede genetic testing of family members.
      • Christiaans I.
      • van Langen I.M.
      • Birnie E.
      • et al.
      Quality of life and psychological distress in hypertrophic cardiomyopathy mutation carriers: a cross-sectional cohort study.
      Relatives with overt HCM will have the same pathogenic HCM mutation as the index patient. Pathogenic mutations may also be identified in other relatives with unknown clinical status. These mutation carriers should be evaluated by physical examination, electrocardiography, and 2-dimensional echocardiography, and if HCM is identified, these individuals should undergo risk stratification (Section 6.3.1). Mutation carriers without evidence of HCM (genotype positive/phenotype negative) are at considerable risk for future development of HCM, and guidelines to evaluate these individuals are discussed below.
      • Maron B.J.
      • Yeates L.
      • Semsarian C.
      Clinical challenges of genotype positive (+)-phenotype negative (−) family members in hypertrophic cardiomyopathy.
      • Maron B.J.
      • Semsarian C.
      Emergence of gene mutation carriers and the expanding disease spectrum of hypertrophic cardiomyopathy.
      Mutation-negative family members and their descendents have no risk for developing HCM and do not need further evaluation. Information from genotyping may help define clinical manifestations and outcomes in specific families with HCM.
      • Niimura H.
      • Bachinski L.L.
      • Sangwatanaroj S.
      • et al.
      Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.
      • Van Driest S.L.
      • Ackerman M.J.
      • Ommen S.R.
      • et al.
      Prevalence and severity of “benign” mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy.
      • Van Driest S.L.
      • Jaeger M.A.
      • Ommen S.R.
      • et al.
      Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy.
      • Rosenzweig A.
      • Watkins H.
      • Hwang D.S.
      • et al.
      Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes.
      • Moolman J.C.
      • Corfield V.A.
      • Posen B.
      • et al.
      Sudden death due to troponin T mutations.
      • Woo A.
      • Rakowski H.
      • Liew J.C.
      • et al.
      Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis.
      • Ho C.Y.
      • Lever H.M.
      • DeSanctis R.
      • et al.
      Homozygous mutation in cardiac troponin T: implications for hypertrophic cardiomyopathy.
      • Chimenti C.
      • Pieroni M.
      • Morgante E.
      • et al.
      Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy.
      When genetic testing is not performed or a mutation is not identified in the index patient, clinical screening of all first-degree family members is important to identify those with unrecognized HCM. Offspring of unaffected individuals do not warrant clinical screening unless prompted by unexpected signs or symptoms. For more information on screening intervals, see Section 5.3.1.

      5.1.1 Genotype-Positive/Phenotype-Negative Patients—Recommendation

      Class I
      1. In individuals with pathogenic mutations who do not express the HCM phenotype, it is recommended to perform serial electrocardiogram (ECG), TTE, and clinical assessment at periodic intervals (12 to 18 months in children and adolescents and about every 5 years in adults), based on the patient’s age and change in clinical status.
      • Christiaans I.
      • Lekanne dit Deprez R.H.
      • van Langen I.M.
      • et al.
      Ventricular fibrillation in MYH7-related hypertrophic cardiomyopathy before onset of ventricular hypertrophy.
      • Andersen P.S.
      • Havndrup O.
      • Hougs L.
      • et al.
      Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives.
      • Christiaans I.
      • Birnie E.
      • van Langen I.M.
      • et al.
      The yield of risk stratification for sudden cardiac death in hypertrophic cardiomyopathy myosin-binding protein C gene mutation carriers: focus on predictive screening.
      • Michels M.
      • Soliman O.I.
      • Phefferkorn J.
      • et al.
      Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers.
      (Level of Evidence: B)
      Genetic screening of first-degree relatives of an index patient with HCM can reveal typically young family members with a mutation (genotype positive) but without cardiac hypertrophy (phenotype negative) (Table 3).
      • Maron B.J.
      • Yeates L.
      • Semsarian C.
      Clinical challenges of genotype positive (+)-phenotype negative (−) family members in hypertrophic cardiomyopathy.
      • Maron B.J.
      • Semsarian C.
      Emergence of gene mutation carriers and the expanding disease spectrum of hypertrophic cardiomyopathy.
      • Ho C.Y.
      • Sweitzer N.K.
      • McDonough B.
      • et al.
      Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy.
      • Rosenzweig A.
      • Watkins H.
      • Hwang D.S.
      • et al.
      Preclinical diagnosis of familial hypertrophic cardiomyopathy by genetic analysis of blood lymphocytes.
      • Maron B.J.
      • Ho C.Y.
      Hypertrophic cardiomyopathy without hypertrophy: an emerging pre-clinical subgroup composed of genetically fnected family members.
      • Poutanen T.
      • Tikanoja T.
      • Jaaskelainen P.
      • et al.
      Diastolic dysfunction without left ventricular hypertrophy is an early finding in children with hypertrophic cardiomyopathy-causing mutations in the beta-myosin heavy chain, alpha-tropomyosin, and myosin-binding protein C genes.
      As the clinical expression of HCM usually increases with age, clinical screening (by physical examination, electrocardiography, and 2-dimensional echocardiography or CMR) of genotype-positive/phenotype-negative individuals is also recommended at the intervals indicated below. Electrocardiographic abnormalities, increased ejection fraction (EF), and delayed myocardial relaxation can precede the onset of hypertrophy.
      • Ho C.Y.
      • Sweitzer N.K.
      • McDonough B.
      • et al.
      Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy.
      • Poutanen T.
      • Tikanoja T.
      • Jaaskelainen P.
      • et al.
      Diastolic dysfunction without left ventricular hypertrophy is an early finding in children with hypertrophic cardiomyopathy-causing mutations in the beta-myosin heavy chain, alpha-tropomyosin, and myosin-binding protein C genes.
      When abnormal, these parameters can indicate early emergence of clinical disease. Information about risk of SCD is limited.
      • Maron B.J.
      • Yeates L.
      • Semsarian C.
      Clinical challenges of genotype positive (+)-phenotype negative (−) family members in hypertrophic cardiomyopathy.
      • Maron B.J.
      • Semsarian C.
      Emergence of gene mutation carriers and the expanding disease spectrum of hypertrophic cardiomyopathy.
      • Christiaans I.
      • Birnie E.
      • van Langen I.M.
      • et al.
      The yield of risk stratification for sudden cardiac death in hypertrophic cardiomyopathy myosin-binding protein C gene mutation carriers: focus on predictive screening.
      • Michels M.
      • Soliman O.I.
      • Phefferkorn J.
      • et al.
      Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers.
      Table 3Proposed clinical screening strategies with echocardiography (and 12-lead ECG) for detection of hypertrophic cardiomyopathy with left ventricular hypertrophy in families
      When pathologic mutations are not identified or genetic testing is either ambiguous or not performed.
      Adapted with permission from Maron et al.
      • Maron B.J.
      • Seidman J.G.
      • Seidman C.E.
      Proposal for contemporary screening strategies in families with hypertrophic cardiomyopathy.
      Age <12 y
       Optional unless
      Malignant family history of premature death from HCM or other adverse complications
      Patient is a competitive athlete in an intense training program
      Onset of symptoms
      Other clinical suspicion of early LV hypertrophy
      Age 12 to 18–21 y
      Age range takes into consideration individual variability in achieving physical maturity and in some patients may justify screening at an earlier age. Initial evaluation should occur no later than early pubescence.125
       Every 12–18 mo
      Age >18–21 y
       At onset of symptoms or at least every 5 y. More frequent intervals are appropriate in families with a malignant clinical course or late-onset HCM.
      ECG, Electrocardiogram; HCM, hypertrophic cardiomyopathy; LV, left ventricular.
      When pathologic mutations are not identified or genetic testing is either ambiguous or not performed.
      Age range takes into consideration individual variability in achieving physical maturity and in some patients may justify screening at an earlier age. Initial evaluation should occur no later than early pubescence.
      • Rigon F.
      • Bianchin L.
      • Bernasconi S.
      • et al.
      Update on age at menarche in Italy: toward the leveling off of the secular trend.
      When family history indicates a high risk for SCD, periodic assessment of arrhythmias (by exercise stress testing or Holter monitoring) in genotype-positive/phenotype-negative individuals may be appropriate. Decisions about participation in competitive athletics must be resolved on a case-by-case basis with the patient and family fully informed about the potential risks
      • Maron B.J.
      • Yeates L.
      • Semsarian C.
      Clinical challenges of genotype positive (+)-phenotype negative (−) family members in hypertrophic cardiomyopathy.
      (Section 6.3.3).

      5.2 Electrocardiography—Recommendations

      Class I
      • 1.
        A 12-lead ECG is recommended in the initial evaluation of patients with HCM. (Level of Evidence: C)
      • 2.
        Twenty-four–hour ambulatory (Holter) electrocardiographic monitoring is recommended in the initial evaluation of patients with HCM to detect ventricular tachycardia (VT) and identify patients who may be candidates for ICD therapy.
        • Maron B.J.
        • McKenna W.J.
        • Danielson G.K.
        • et al.
        American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy.
        • Elliott P.M.
        • Gimeno J.R.
        • Tome M.T.
        • et al.
        Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy.
        • Maron B.J.
        • Savage D.D.
        • Wolfson J.K.
        • et al.
        Prognostic significance of 24 hour ambulatory electrocardiographic monitoring in patients with hypertrophic cardiomyopathy: a prospective study.
        • Monserrat L.
        • Elliott P.M.
        • Gimeno J.R.
        • et al.
        Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients.
        (Level of Evidence: B)
      • 3.
        Twenty-four–hour ambulatory (Holter) electrocardiographic monitoring or event recording is recommended in patients with HCM who develop palpitations or lightheadedness.
        • Maron B.J.
        • McKenna W.J.
        • Danielson G.K.
        • et al.
        American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy.
        • Elliott P.M.
        • Gimeno J.R.
        • Tome M.T.
        • et al.
        Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy.
        • Maron B.J.
        • Savage D.D.
        • Wolfson J.K.
        • et al.
        Prognostic significance of 24 hour ambulatory electrocardiographic monitoring in patients with hypertrophic cardiomyopathy: a prospective study.
        (Level of Evidence: B)
      • 4.
        A repeat ECG is recommended for patients with HCM when there is worsening of symptoms. (Level of Evidence: C)
      • 5.
        A 12-lead ECG is recommended every 12 to 18 months as a component of the screening algorithm for adolescent first-degree relatives of patients with HCM who have no evidence of hypertrophy on echocardiography. (Level of Evidence: C)
      • 6.
        A 12-lead ECG is recommended as a component of the screening algorithm for first-degree relatives of patients with HCM. (Level of Evidence: C)
      Class IIa
      • 1.
        Twenty-four–hour ambulatory (Holter) electrocardiographic monitoring, repeated every 1 to 2 years, is reasonable in patients with HCM who have no previous evidence of VT to identify patients who may be candidates for ICD therapy.
        • Monserrat L.
        • Elliott P.M.
        • Gimeno J.R.
        • et al.
        Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients.
        (Level of Evidence: C)
      • 2.
        Annual 12-lead ECGs are reasonable in patients with known HCM who are clinically stable to evaluate for asymptomatic changes in conduction or rhythm (ie, AF). (Level of Evidence: C)
      Class IIb
      • 1.
        Twenty-four–hour ambulatory (Holter) electrocardiographic monitoring might be considered in adults with HCM to assess for asymptomatic paroxysmal AF/atrial flutter. (Level of Evidence: C)
      The 12-lead ECG