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Hypertrophic Cardiomyopathy: A Review

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common heart disease with a genetic origin, and its main characteristic is left ventricular hypertrophy that occurs in the absence of other conditions that trigger this change. HCM may present from asymptomatic forms to manifestations of sudden cardiac death and severe heart failure. Contemporary high-resolution imaging methods and more accurate clinical scores have been used and developed to provide a prognostic assessment and adequate functional assessments, as well as to allow for the stratification of clinical severity. These aspects will be addressed in this review, along with other classic topics inherent to the study of this disease.

Keywords
Cardiomyopathy, Hypertrophic/genetics; Sudden Cardiac Death; Heart failure; Echocardiography/methods; Hypertrophy, Left Ventricle

Resumo

A cardiomiopatia hipertrófica (CMH) é a doença cardíaca de origem genética mais comum, cuja principal característica consiste na hipertrofia ventricular esquerda que acontece na ausência de outras patologias que desencadeiam tal alteração. A CMH pode se apresentar desde formas assintomáticas até manifestações de morte cardíaca súbita e de insuficiência cardíaca refratária. Métodos de imagem contemporâneos de alta resolução e escores clínicos mais acurados vêm sendo utilizados e desenvolvidos no sentido de propiciar uma avaliação prognóstica e funcional mais adequada, bem como possibilitar a estratificação dos casos de maior gravidade. Nesta revisão, serão abordados esses aspectos, entre outros tópicos clássicos inerentes ao estudo dessa doença.

Palavras-chave
Cardiomiopatia Hipertrófica/genética; Morte Súbita; Insuficiência Cardíaca; Ecocardiografia/métodos; Hipertrofia Ventricular

Introduction

Hypertrophic cardiomyopathy (HCM) is a disease with a genetically determined cause that leads to structural changes in the cardiac conformation (Figure 1). The main anatomical characteristic of this disease is left ventricular hypertrophy (LVH) with various morphologies in the absence of other conditions that justify this finding.11. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. 2014; 35(39):2733–2779.

Figure 1
Schematic of a normal heart (left panel) and a heart with HCM (right panel).

The prevalence of HCM is relatively frequent, occurring in about 0.2% of the adult population.22. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. 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. Circulation. 1995; 92(4):785-789. Its clinical presentation is extremely variable, ranging from asymptomatic forms to advanced heart failure (HF), among other presentations that culminate with sudden death.33. Marian AJ. Hypertrophic cardiomyopathy: from genetics to treatment. Eur J Clin Invest. 2010; 40(4):360-369.

On the other hand, advances in the treatment of HCM have resulted in a current mortality rate of less than 1% per year.44. Maron BJ, Ommen SR, Semsarian C, Spirito P, Olivotto I, Maron MS. Hypertrophic Cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol. 2014; 64(1):83-99.,55. Cardim N, Brito D, Lopes LR, Freitas A, Araújo C, Belo A, Gonçalves L, Mimoso J, Olivotto I, Elliott P, Madeira H. The Portuguese Registry of Hypertrophic Cardiomyopathy: Overall results. Rev Port Cardiol. 2018;37(1):1-10.

Thus, it is a subject of great interest due to its significant prevalence and the importance of early identification of at-risk groups, such as competitive athletes.

Genetic bases

Genetic analyses of HCM have identified a series of mutations in over 11 genes encoding sarcomeric proteins.66. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet. 2013; 381(9862): 242-255. HCM can occur in a dominant autosomal inheritance pattern with variable expressivity and penetrance related to age or as a new mutation in non-family related cases.77. Alcalai R, Seidman JG, Seidman CE. Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics. 2008; 19(1):104-110.,88. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol. 2012;60(8):705-715. The predominant mutation is the missense mutation, in which one nucleic acid is replaced by another, with a subsequent modification of the translated amino acid and the functional property of the resulting protein. Insertions and deletions are also common mutations identified as being involved in the pathogenesis of HCM that trigger the production of abnormal proteins.88. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol. 2012;60(8):705-715.

Patients with HCM are found to have some type of genetic alteration in approximately one-half cases.99. Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med. 2008; 358(18):1899-1908.,1010. Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice. Circulation. 2011; 123(9):1021-1037.

Most mutations affect the genes encoding the contractile proteins of the cardiac sarcomere: troponin T and I myosin light chain, myosin heavy chains alpha and beta, myosin-binding protein C, alpha-actin, alpha-tropomyosin and titin. However, mutations in nonsarcomeric protein-coding genes have already been identified in patients with HCM.1111. Marian AJ, Roberts R. The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2001; 33(4):655. The genes most commonly related to the development of the disease are myosin heavy chain beta (MYH7), myosin-binding protein C (MYBPC3) and troponin T (TNNT2)1212. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003; 107(17):2227-2232. (Figure 2).

Figure 2
Distribution of gene mutations in HCM (Adapted from Maron BJ et al.88. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol. 2012;60(8):705-715.)

The pathogenicity of a mutation is evaluated probabilistically using a series of criteria that will determine the risk of developing HCM.1313. Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med. 2008; 10(4):294-300.

The concept of phenocopies in the HCM context is also important to highlight. These patients have a CHM phenotype without the CMH genetic mutations, but instead present with some other disease leading to a similar heart condition, such as Fabry disease, LAMP2 cardiomyopathy, PRKAG2 and/or amyloidosis.

Pathological findings

Histopathological analysis of HCM tissue shows hypertrophied myocardial fibers distributed in a disorganized pattern and interposed in a variable amount of interstitial fibrosis1414. Shirani J, Pick R, Roberts WC, Maron BJ. Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death. J Am Coll Cardiol. 2000;35(1):36-44. (Figure 3).

Figure 3
Myocyte disarray in the myocardial tissue of a patient with HCM.

In addition, intramural coronary arterioles are structurally abnormal and present a decreased intraluminal area with deteriorated vasodilatory capacity, which promotes inefficient blood flow during stress.1515. Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol.1986; 8(3):545–557. Over time, repeated episodes of ischemia lead to cell death, and repair is mediated by replacement with fibrotic tissue.1414. Shirani J, Pick R, Roberts WC, Maron BJ. Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death. J Am Coll Cardiol. 2000;35(1):36-44.

Different types of anatomical presentations of HCM have been reported. The most common type is asymmetric septal hypertrophy (present in > 75% of cases), followed by apical, concentric, medioventricular and lateral presentations.1616. Albanesi Fº FM. Cardiomiopatia Hipertrófica. Conceito e Classificação. Arq Bras Cardiol. 1996;66(2):103-105.

Pathophysiology

HCM-related symptoms are related to the combination of diastolic dysfunction, obstruction of the left ventricular outflow tract (LVOT), mitral regurgitation, myocardial ischemia and arrhythmias. The most common factor contributing to the development of LVOT obstruction is systolic anterior motion (SAM) of the mitral valve against the IVS. SAM occurs due to the high speed of blood flow through the LVOT that drags the anterior mitral valve leaflet toward the interventricular septum, resulting in a direct impediment to blood flow through the outflow tract.1717. Spirito P, Seidman CE, McKenna WJ, Maron BJ. The management of hypertrophic cardiomyopathy. N Engl J Med. 1997;336(11):775-785.

In addition, the combination of myocyte disarray, autonomic disorder, LVH, ischemia and myocardial fibrosis generates a sufficient arrhythmogenic substrate for the development of the main arrhythmias observed in patients with HCM.22. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. 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. Circulation. 1995; 92(4):785-789.

These characteristics do not appear simultaneously, and a 4-stage classification has been proposed to assist with the diagnosis and management of patients: nonhypertrophic HCM, classic phenotype, adverse remodeling and overt dysfunction.1818. Olivotto I, Cecchi F, Poggesi C, Yacoub MH. Patterns of Disease Progression in Hypertophic Cardiomyopathy. Circ Heart Fail. 2012;5:535-546. As the patient advances through the stages, he experiences a loss of ejection fraction, an increase in the left ventricular mass, a worsening of microvascular and diastolic dysfunction, an intensification of symptoms and a loss of a prior left ventricular outflow tract obstruction, which usually begins in stage 2.

Clinical presentations

HCM-related symptoms are related to the existing profiles of the disease, including an asymptomatic presentation, sudden cardiac death-ventricular arrhythmias, obstruction, heart failure with preserved ejection fraction, atrial fibrillation/stroke and heart failure with reduced ejection fraction. Although many patients with HCM have no symptoms or only experience minor symptoms, others may present dyspnea under stress, fatigue, chest pain, pre-syncope and syncope, during or shortly after stress, and heart palpitations.1919. Wigle ED. Cardiomyopathy: The diagnosis of hypertrophic cardiomyopathy. Heart. 2001; 86(6):709-714.

A well-established correlation has been observed between the presence or magnitude of the LVOT obstruction and the presence of symptoms.2020. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic cardiomyopathy. Clinical spectrum and treatment. Circulation. 1995;92(7):1680-1692.

For most patients with HCM, LVH is not progressive and is compatible with a normal lifespan, with an annual mortality rate of approximately 1%.2121. Maron BJ, Casey SA, Poliac LC, Gohman TE, Almquist AK, Aeppli DM. Clinical course of hypertrophic cardiomyopathy in a regional United States cohort. JAMA. 1999;281(7):650-655.

On the other hand, a small group of patients present a risk of developing symptoms related to the progression of systolic heart failure, sudden death, and atrial fibrillation related to thromboembolic phenomena.2222. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA. 2002; 287(10):1308-1320.

The presence of a pressure gradient in the LVOT at rest or provoked by exercise occurs in most patients with HCM.2323. Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, Cecchi F, Udelson JE, Maron BJ. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006; 114(21):2232-2239. Significant obstruction at rest is an independent factor for a worse prognosis and progression to heart failure.2424. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. 2003;348(4):295-303.

The physical examination of patients with HCM may reveal normal findings or the presence of various signs, such as the fourth heart sound (S4), regurgitation systolic heart murmur on the lower left sternal border, paradoxical splitting of second heart sound (S2), heaving apical impulse, and systolic thrill. Additionally, patients with obstruction of the LVOT may present an ejection systolic murmur at the left sternal edge that usually radiates to the right upper sternal edge and may increase upon standing from the squatting position and in the Valsalva maneuver.

The arterial pulse may be bifid and present a dome-shaped systolic peak, while a prominent “a” wave is detected in the venous pulse.

Complementary examinations

  • Electrocardiogram (ECG): This test should be performed in all patients with suspected HCM. A normal ECG is unusual, as it was observed in less than 10% of patients with HCM, and this test is very sensitive for identifying the disease.2525. Ryan MP, Cleland JG, French JA, Joshi J, Choudhury L, Chojnowska L, Michalak E, al-Mahdawi S, Nihoyannopoulos P, Oakley CM. The standard electrocardiogram as a screening test for hypertrophic cardiomyopathy. Am J Cardiol. 1995;76(10):689-694. This group of patients tends to present a better prognosis than patients who present electrocardiographic alterations.2626. McLeod CJ, Ackerman MJ, Nishimura RA, Tajik AJ, Gersh BJ, Ommen SR. Outcome of patients with hypertrophic cardiomyopathy and a normal electrocardiogram. J Am Coll Cardiol. 2009; 54(3):229-233. The most common abnormal pattern is the presence of localized or diffuse alterations in ventricular repolarization. Other findings may include signs of left ventricular hypertrophy, the inversion of T wave at the left leads, and an increase in the left atrium. Deep and narrow “Q” waves may occur in V5 and V6.

  • Echocardiogram: An echocardiogram is an essential examination both for diagnostic confirmation and for evolutionary, functional and prognostic evaluations.2727. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. 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. J Am Coll Cardiol. 2011; 58(25):e212-e260. The transthoracic echocardiogram can show the heart morphology, estimate the systolic and diastolic function, assess the presence and severity of the gradient in the LVOT, and determine the degree of mitral regurgitation. The major echocardiographic findings associated with HCM are LVH (particularly if it is asymmetrical and involving the anterolateral wall or septum), an increased gradient in the LVOT, and the systolic anterior motion of the mitral leaflet (Figure 4).

Figure 4
Transthoracic echocardiogram showing asymmetrical hypertrophy of the interventricular septum. IVS: interventricular septum; LV: left ventricle; LA: left atrium; AO: aortic root. (Serviço de Ecocardiografia do HC – Faculdade de Medicina de Botucatu – UNESP).

Patients who remain symptomatic and do not present an obstruction at rest may undergo stress echocardiography to induce a gradient and subsequently adjust the therapeutic management and treatment according to the result.2323. Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, Cecchi F, Udelson JE, Maron BJ. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006; 114(21):2232-2239.

  • Holter-ECG: This test is conducted as part of the stratification of the risk of developing ventricular arrhythmias and sudden death, as well as to investigate palpitations and in patients with suspected atrial fibrillation.

  • Exercise stress test: This test is typically performed for risk stratification by measuring the blood pressure response to exercise and to investigate ischemia and arrhythmias.

  • Cardiac Magnetic Resonance (CMR): CMR provides high-resolution images for evaluating cardiac structures. In addition to being able to identify hypertrophy in segments that are not displayed in echocardiography, it also shows myocardial fibrosis areas, which are usually detected through late gadolinium enhancement, and are one of the sudden death risk factors, enabling better characterization of structural abnormalities in the mitral valve apparatus2828. Bogaert J, Olivotto I. MR Imaging in Hypertrophic Cardiomyopathy: From Magnet to Bedside. Radiology. 2014; 273(2):329-348.3030. Nagueh SF, Bierig SM, Budoff MJ, Desai M, Dilsizian V, Eidem B, Goldstein SA, Hung J, Maron MS, Ommen SR, Woo A. American Society of Echocardiography Clinical Recommendations for Multimodality Cardiovascular Imaging of Patients with Hypertrophic Cardiomyopathy Endorsed by the American Society of Nuclear Cardiology, Society for Cardiovascular Magnetic Resonance, and Society of Cardiovascular Computed Tomography. J AM Soc Echocardiogr. 2011;24(5):473-498. (Figure 5).

Figure 5
CMR of a patient with HCM and the nonobstructive asymmetric septal presentation. LA: left atrium; RA: right atrium; IVS: interventricular septum; LV: left ventricle; RV: right ventricle; LVOT: left ventricular outflow tract. (Courtesy of the Department of Radiology of the HC – Faculdade de Medicina de Botucatu – UNESP).

Treatment

The treatment is initiated with preventive measures, such as avoiding intravascular volume depletion and restricting the practice of intense physical exercise, with the recommended activity level being individualized for each patient.3131. Budts W, Börjesson M, Chessa M, van Buuren F, Trigo Trindade P, Corrado D, Heidbuchel H, Webb G, Holm J, Papadakis M. Physical activity in adolescents and adults with congenital heart defects: individualized exercise prescription. Eur Heart J. 2013; 34(47):3669-3674.,3232. Longmuir PE, Brothers JA, de Ferranti SD, Hayman LL, Van Hare GF, Matherne GP, Davis CK, Joy EA, McCrindle BW. Promotion of physical activity for children and adults with congenital heart disease: a scientific statement from the American Heart Association. Circulation. 2013; 127(21):2147-2159. Additional measures include the maintenance of negative inotropic drugs, avoiding the use of vasodilators and the use of an appropriate treatment for tachyarrhythmias.

Drug therapy

Pharmacological therapy is the first-line treatment for patients with symptoms of HF related to an LVOT obstruction.2626. McLeod CJ, Ackerman MJ, Nishimura RA, Tajik AJ, Gersh BJ, Ommen SR. Outcome of patients with hypertrophic cardiomyopathy and a normal electrocardiogram. J Am Coll Cardiol. 2009; 54(3):229-233.

The use of medications is not recommended before the development of symptoms, since evidence does not indicate that pharmacological therapy changes the natural history of asymptomatic patients.

The first-line treatment is beta-blockers. Currently, clinical trials have not indicated preference for a specific beta-blocker, as they have not been compared. However, studies have reported the benefits of propranolol and sotalol, although the latter is a class 3 anti-arrhythmic agent, in reducing the symptoms and decreasing arrhythmias.

Upon the failure of beta-blockers to alleviate the symptoms, the second option is disopyramide, which may increase effort tolerance, sometimes at the cost of anticholinergic side effects, such as urinary retention and dry mouth.

When beta-blockers are unable to be used, another option is verapamil, although this treatment must be carefully monitored in patients with severe obstruction due to the risk of pulmonary edema.

Diltiazem remains the last option when the previous therapies were unsuccessful.11. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. 2014; 35(39):2733–2779.

Patients who present an LVOT obstruction and persistent symptoms of HF despite monotherapy may benefit from the combination of disopyramide with the current treatment implemented3333. Sherrid MV, Barac I, McKenna WJ, Elliott PM, Dickie S, Chojnowska L, Casey S, Maron BJ. Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005; 45(8):1251-1258. (Figure 6). Patients treated with disopyramide should undergo basal and periodic ECG during follow-up to monitor the QTc interval. The use of disopyramide should be avoided in patients with prostatic hyperplasia due to its anticholinergic effect.

Figure 6
Flow chart to determine the appropriate medication for patients with HCM.

Arrhythmias and prevention of sudden death

Atrial fibrillation (AF) is a relatively common arrhythmia in patients with HCM that potentially results in major adverse clinical outcomes, and its incidence is approximately five times greater in patients with HCM than in the general population.3434. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation. 2001; 104(21):2517-2524.

AF is usually poorly tolerated in patients with HCM due to the reduction in diastolic filling time and loss of atrial contraction, factors that are often associated with diastolic dysfunction and are present in a large proportion of these patients. The development of AF is associated with a worsening of the functional class of these patients and with symptoms of HF.

In addition, AF is a marker of poor prognosis for patients with HCM3535. Cecchi F, Olivotto I, Montereggi A, Santoro G, Dolara A, Maron BJ. Hypertrophic cardiomyopathy in Tuscany: clinical course and outcome in an unselected regional population. J Am Coll Cardiol. 1995;26(6):1529-1536. and signals a significantly increased risk of acute cerebrovascular events.3636. Higashikawa M, Nakamura Y, Yoshida M, Kinoshita M. Incidence of ischemic strokes in hypertrophic cardiomyopathy is markedly increased if complicated by atrial fibrillation. Jpn Circ J. 1997;61(8):673-681.

The treatment of AF in patients with HCM is similar to the general recommendations for treating AF in patients without HCM, and both the control of rhythm and heart rate are available options,3737. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). Circulation. 2006; 114(7):e257-e354. with the choice of the best strategy being based on the clinical profile of each patient. Since the risk of thromboembolic events is increased in patients who develop AF, the recommendation of anticoagulant treatment in this group of patients is reasonable and indicated in most cases, regardless of the risk stratification based on the CHADS2 score.2727. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. 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. J Am Coll Cardiol. 2011; 58(25):e212-e260.

Ventricular arrhythmias are common in patients with HCM, including ventricular extrasystoles (VES), non-sustained ventricular tachycardia (NSVT), ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD). The first two types occur more frequently in patients with HCM.3838. Adabag AS, Casey SA, Kuskowski MA, Zenovich AG, Maron BJ. Spectrum and prognostic significance of arrhythmias on ambulatory. Holter electrocardiogram in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005; 45(5):697-704.

The treatment of VES is only necessary in patients who present symptoms, since the presence of this condition alone does not confer an increased risk of SCD.3939. Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients. J Am Coll Cardiol. 2003; 42(5):873-879.

NSVT occurs more frequently in patients with higher degrees of LVH, in patients with more advanced functional classes (III/IV) and in older individuals. However, its presence in young individuals confers a greater risk of SCD. NSVT episodes are more frequent during sleep or during other periods of vagal hyperactivity. Patients with HCM who present NSVT during a Holter-ECG exhibit an increased risk of SCD,3939. Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients. J Am Coll Cardiol. 2003; 42(5):873-879. and this risk is even higher if the episodes of NSVT are prolonged, repetitive, or associated with symptoms of low cardiac output.4040. Cecchi F, Olivotto I, Montereggi A, Squillatini G, Dolara A, Maron BJ. Prognostic value of non-sustained ventricular tachycardia and the potential role of amiodarone treatment in hypertrophic cardiomyopathy: assessment in an unselected non-referral based patient population. Heart. 1998;79(4):331-336. When adjuvant pharmacological therapy is proposed to reduce symptoms or the incidence of ventricular arrhythmias, the medicine that is most commonly used as the initial therapy is the beta-blocker, and amiodarone has been used to treat refractory cases.4141. McKenna WJ, Harris L, Rowland E, Kleinebenne A, Krikler DM, Oakley CM, Goodwin JF. Amiodarone for long-term management of patients with hypertrophic cardiomyopathy. Am J Cardiol. 1984;54(7):802-810. In patients at high risk of developing SCD, no drug is a suitable alternative to the implantation of an implantable cardioverter-defibrillator (ICD).

Clinically documented, sustained VT is usually rare and presents mostly as palpitations, pre-syncope or syncope. In the absence of the identification of a possible triggering factor, it is considered a major risk factor for SCD. Most patients who develop this type of arrhythmia receive the ICD as a secondary prevention strategy.

Risk stratification for SCD should be performed in all patients with HCM. The first two major risk factors for this condition are prior aborted cardiac arrest and spontaneous sustained VT.2727. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. 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. J Am Coll Cardiol. 2011; 58(25):e212-e260. Patients who survive an episode of VF or VT are at very high risk of recurring events, which justifies the implant of an ICD for secondary prevention in these patients.4242. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Page RL, Riegel B, Tarkington LG, Yancy CW. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation. 2008; 117(21):e350-408.

Additional major risk factors for primary prevention have been identified, since the majority of patients do not survive the first episode of ventricular arrhythmia,4343. Spirito P, Autore C. Management of hypertrophic cardiomyopathy. BMJ. 2006; 332(7552):1251-1255. and because it may be the first manifestation of the disease in asymptomatic individuals.

Eight major factors are more commonly considered in the primary prevention of SCD:4444. O'Mahony C, Elliot PM. Prevention of sudden cardiac death in hypertrophic cardiomyopathy. Heart. 2014;100(3):254-260.

  • A family history (FH) of HCM related to sudden cardiac death4545. McKenna W, Deanfield J, Faruqui A, England D, Oakley C, Goodwin J. Prognosis in hypertrophic cardiomyopathy: role of age and clinical, electrocardiographic and hemodynamic features. Am J Cardiol. 1981;47(3):532-538. (particularly if early SCD is present or multiple individuals within the same family are affected);

  • Syncope that is not explained by another cause;4646. Priori SG, Aliot E, Blomstrom-Lundqvist C, Bossaert L, Breithardt G, Brugada P, Camm AJ, Cappato R, Cobbe SM, Di Mario C, Maron BJ, McKenna WJ, Pedersen AK, Ravens U, Schwartz PJ, Trusz-Gluza M, Vardas P, Wellens HJ, Zipes DP. Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J. 2001; 22(16):1374-1450.

  • NSVT3838. Adabag AS, Casey SA, Kuskowski MA, Zenovich AG, Maron BJ. Spectrum and prognostic significance of arrhythmias on ambulatory. Holter electrocardiogram in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005; 45(5):697-704. (particularly if it is associated with symptoms or occurs in young individuals);

  • Abnormal response of blood pressure in patients aged less than 40 years or patients with a family history of early SCD;4747. Sadoul N, Prasad K, Elliott PM, Bannerjee S, Frenneaux MP, McKenna WJ. Prospective prognostic assessment of blood pressure response during exercise in patients with hypertrophic cardiomyopathy. Circulation. 1997; 96(9):2987-2991.

  • Severe LVH (≥30 mm),4848. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med. 2000;342(24):1778-1785. particularly in patients aged less than 30 years;

  • Contrast CMR showing late gadolinium enhancement - identified fibrosis, usually greater than 15% of the LV mass;

  • Systolic dysfunction with an ejection fraction less than 50%; and

  • Left ventricular apical aneurysm, regardless of size.4949. Maron MS, Rowin EJ, Wessler BS, Mooney PJ, Fatima A, Patel P, Koethe BC, Romashko M, Link MS, Maron BJ. Enhanced American College of Cardiology/American Heart Association Strategy for Prevention of Sudden Cardiac Death in High-Risk Patients With Hypertrophic Cardiomyopathy. JAMA Cardiol. 2019;4(7):644-657.

Possible risk factors include the patient's age at the time of diagnosis, a pressure gradient greater than 30 mmHg in the LVOT, diastolic dysfunction, myocardial ischemia and the presence of high-risk genotypes, among others (Table 1).

Table 1
Predictors of SCD in patients with HCM

Patients with two or three major risk factors have an aborted SCD rate of approximately 5% per year, which justifies the implantation of an ICD in this population.5050. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK, Daubert JP, Bardy GH, Favale S, Rea RF, Boriani G, Estes NA 3rd, Spirito P. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000; 342(6):365-373.

Thus, most professional societies and organizations recommend that patients with HCM presenting with two or more major risk factors receive an ICD for the primary prevention of SCD2727. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. 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. J Am Coll Cardiol. 2011; 58(25):e212-e260., although studies have shown that the presence of a major risk factor justifies the implantation of an ICD.4242. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Page RL, Riegel B, Tarkington LG, Yancy CW. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation. 2008; 117(21):e350-408.,5151. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE, Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes NA 3rd, Favale S, Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MV, Buja G, Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA. 2007; 298(4):405-412.

Recently, a new model for risk stratification has been developed. This score uses an equation that introduces continuous variables such as age, left ventricular shortening fraction, left ventricular maximum thickness, maximum gradient in the LVOT, and left atrial diameter, and proved to be promising in the search for a more accurate method to determine the prognosis of patients with HCM.5252. O'Mahony C, Jichi F, Pavlou M, Monserrat L, Anastasakis A, Rapezzi C, Biagini E, Gimeno JR, Limongelli G, McKenna WJ, Omar RZ, Elliott PM; Hypertrophic Cardiomyopathy Outcomes Investigators. A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM Risk-SCD). Eur Heart J. 2014; 35(30): 2010-2020.

Invasive therapy

A pressure gradient in the LVOT occurs in most patients with HCM,2323. Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, Cecchi F, Udelson JE, Maron BJ. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006; 114(21):2232-2239. and represents a poor prognostic factor and predictor of the emergence of HF symptoms when present at rest.2424. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. 2003;348(4):295-303. Patients with an LVOT obstruction and LV/aorta pressure gradient (either at rest or induced) > 50 mmHg and that persist with limiting symptoms despite the use of the maximum optimized drug therapy are candidates for invasive septal reduction.

Septal myectomy is a good option when the mitral valve or papillary muscle abnormalities must be repaired or myocardial revascularization is required, in addition to directly removing the septal muscle and expanding the LVOT.5353. Heric B, Lytle BW, Miller DP, Rosenkranz ER, Lever HM, Cosgrove DM. Surgical management of hypertrophic obstructive cardiomyopathy. Early and late results. J Thorac Cardiovasc Surg. 1995;110(1):195-206. Myectomy generally results in the resolution of the gradient in the LVOT and improves the symptoms of patients,5454. Smedira NG, Lytle BW, Lever HM, Rajeswaran J, Krishnaswamy G, Kaple RK, Dolney DO, Blackstone EH. Current effectiveness and risks of isolated septal myectomy for hypertrophic obstructive cardiomyopathy. Ann Thorac Surg. 2008; 85(1):127-133. in addition to being associated with excellent long-term survival.5555. Ommen SR, Maron BJ, Olivotto I, Maron MS, Cecchi F, Betocchi S, Gersh BJ, Ackerman MJ, McCully RB, Dearani JA, Schaff HV, Danielson GK, Tajik AJ, Nishimura RA. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005; 46(3):470-476.

Percutaneous alcohol septal ablation is also a good alternative, as no meta-analysis has favored one method to date. It is particularly indicated when myectomy should not be conducted due to a high surgical risk or the desire of the patient. This procedure reduces the LVOT obstruction, promotes improvement in the functional class, and increases exercise capacity.5656. Alam M, Dokainish H, Lakkis N. Alcohol septal ablation for hypertrophic obstructive cardiomyopathy: a systematic review of published studies. J Interv Cardiol. 2006;19(4):319-327. Patients subjected to alcohol ablation present a five-year survival rate that is comparable to patients subjected to septal myectomy and to the general population.5757. Sorajja P, Ommen SR, Holmes DR Jr, Dearani JA, Rihal CS, Gersh BJ, Lennon RJ, Nishimura RA. Survival after alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation 2012; 126(20):2374-2380.

The main advantage of septal myectomy compared with alcohol ablation are: reduced need for implantation of a definitive pacemaker (PM) due an advanced atrial-ventricular block, reduced need for reintervention because of the recurrence of the LVOT obstruction, and reduced LV/aorta gradient after the procedure.5858. Alam M, Dokainish H, Lakkis NM. Hypertrophic obstructive cardiomyopathy-alcohol septal ablation vs. myectomy: a meta-analysis. Eur Heart J. 2009;30(9):1080-1087. In addition, in contrast to septal ablation, septal myectomy has been shown to reduce the risks of SCD and inappropriate discharges of the ICD.5959. McLeod CJ, Ommen SR, Ackerman MJ, Weivoda PL, Shen WK, Dearani JA, Schaff HV, Tajik AJ, Gersh BJ. Surgical septal myectomy decreases the risk for appropriate implantable cardioverter defibrillator discharge in obstructive hypertrophic cardiomyopathy. Eur Heart J. 2007;28(21):2583-2588.

The implantation of a DDD bicameral PM is a reasonable option during myectomy to reduce the gradient in the LVOT and improve symptoms related to this condition. However, this indication is restricted to patients who already have a bicameral device for other indications, since data on the long-term effects of right ventricle pacing on an HCM left ventricle are unavailable, and the benefit is restricted to only a small subset of patients.11. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. 2014; 35(39):2733–2779.,6060. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson ME, Kieval RS. Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (M-PATHY). Circulation. 1999;99(22):2927-2933.

Family screening

Considering the genetic cause of HCM, close relatives of affected individuals should be evaluated periodically due to the possibility of inheriting the disease. The evaluation consists of anamnesis, physical examination, ECG and echocardiogram, as a strategy for early detection of HCM.6161. Maron BJ, Yeates L, Semsarian C. Clinical challenges of genotype positive (+)-phenotype negative (-) family members in hypertrophic cardiomyopathy. Am J Cardiol. 2011; 107(4):604-608. Evaluations every 12-18 months are recommended, starting at the age of 12, and every 5 years beginning at the age of 18.6262. Maron BJ, Seidman JG, Seidman CE. Proposal for contemporary screening strategies in families with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004; 44(11):2125-2132. Echocardiogram with tissue Doppler has been shown to detect alterations in ventricular contraction and relaxation that may predict the emergence of myocardial dysfunction in these patients.6363. Nagueh SF, Bachinski LL, Meyer D, Hill R, Zoghbi WA, Tam JW, Quiñones MA, Roberts R, Marian AJ. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation. 2001; 104(2):128-130. However, the presence of these abnormalities is not considered in the diagnosis of HCM.

Genetic tests are not routinely performed in family screening, except in situations where the mutation causing the HCM has been identified in the index case. In this situation, the genetic status of the family members should be determined. However, the mutation is generally only detected in approximately 35% of all patients. On the other hand, if the index case has the mutation and the family member does not, the likelihood of disease onset is very low.44. Maron BJ, Ommen SR, Semsarian C, Spirito P, Olivotto I, Maron MS. Hypertrophic Cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol. 2014; 64(1):83-99.

Endocarditis prophylaxis

Patients with HCM present a higher risk of developing infective endocarditis (IE) than patients without HCM, according to a study showing an increased incidence of mitral valve IE in patients with obstructive HCM and with increased size of the left atrium.6464. Spirito P, Rapezzi C, Bellone P, Betocchi S, Autore C, Conte MR, Bezante GP, Bruzzi P. Infective endocarditis in hypertrophic cardiomyopathy: prevalence, incidence, and indications for antibiotic prophylaxis. Circulation. 1999;99(16):2132-2137. However, recent reviews of international guidelines do not recommend the routine administration of prophylaxis for patients with HCM.11. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. 2014; 35(39):2733–2779. On the other hand, specialists' opinions are still in favor of maintaining the prophylaxis for endocarditis in this group of patients before dental procedures, particularly in patients with obstructive HCM.

  • Sources of Funding
    There were no external funding sources for this study.
  • Study Association
    This study is not associated with any thesis or dissertation work.

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Publication Dates

  • Publication in this collection
    07 Dec 2020
  • Date of issue
    Nov 2020
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