Diagnostic evaluation of hipertrophic cardiomyopathy in its clinical and preclinical phases

Mattos, Beatriz Piva e; Torres, Marco Antonio Rodrigues; Freitas, Valéria Centeno de

doi:10.1590/S0066-782X2008001300009

Abstracts

Hypertrophic cardiomyopathy is a familial, genetic disease caused by mutations in genes encoding sarcomeric proteins. It is characterized by various deGrees of left ventricular hypertrophy, usually diffuse, predominantly involving the interventricular septum. The asymptomatic forms with mild or no segmental hypertrophy makes it difficult to establish the diagnosis and screening for familial forms. Its high penetrance is often incomplete and, as a result, 20% to 30% of adults who carry disease-causing gene mutations do not express the phenotype. The susceptibility to sudden death and likelihood of late expression makes establishing a preclinical diagnosis all the more important. The use of Doppler echocardiography and magnetic resonance imaging, in conjunction with a detailed ECG analysis, may be useful in this process. Molecular genetic studies can identify mutations in 60% to 80% of the cases. However, its complex, time-consuming and costly nature, coupled with an inadequate assessment of genotype-phenotype relationships, limits its routine application. Major advances in imaging methods and the introduction of more simplified molecular techniques may contribute to clinical and preclinical diagnosis of hypertrophic cardiomyopathy, in addition to allowing implementation of therapeutic strategies to prevent or delay the development of the disease.

Cardiomyopathy, hypertrophic; cardiomyopathy, hypertrophic, familial; hypertrophy, left ventricular

A cardiomiopatia hipertrófica é uma doença de origem genética e caráter familiar, causada por mutações em genes codificantes de proteínas do sarcômero. Determina hipertrofia ventricular esquerda de grau variável, geralmente difusa, com predominante acometimento do septo interventricular. A ocorrência de formas assintomáticas com hipertrofia segmentar, de grau leve ou ausente, dificulta o diagnóstico e o rastreamento de formas familiares. A penetrância elevada costuma ser incompleta, o que faz com que 20% a 30% dos adultos carreadores de mutações gênicas não expressem o fenótipo. A suscetibilidade à morte súbita e a possibilidade de expressão tardia tornam relevante o diagnóstico em fase pré-clínica. A investigação por meio do ecocardiograma Doppler e da ressonância magnética adicionada à análise detalhada do eletrocardiograma pode contribuir nesse processo. O diagnóstico genético-molecular identifica mutações em 60% a 80% dos casos. A complexidade, a demora e o elevado custo, aliados à insuficiente avaliação das relações genótipo/fenótipo restringem sua aplicação de rotina. O aprimoramento dos métodos de imagem e a introdução de técnicas moleculares mais simplificadas devem favorecer o diagnóstico clínico e pré-clínico da cardiomiopatia hipertrófica e possibilitar a futura introdução de medidas terapêuticas que possam impedir ou retardar o desenvolvimento da doença.

Hipertrofia do ventrículo esquerdo; cardiomiopatia hipertrófica familiar; cardiomiopatia hipertrófica

REVIEW ARTICLE

Diagnostic evaluation of hypertrophic cardiomyopathy in its clinical and preclinical phases

Beatriz Piva e Mattos; Marco Antonio Rodrigues Torres; Valéria Centeno de Freitas

Serviço de Cardiologia do Hospital de Clínicas de Porto Alegre, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS - Brazil

Mailing address

ABSTRACT

Hypertrophic cardiomyopathy is a familial, genetic disease caused by mutations in genes encoding sarcomeric proteins. It is characterized by various deGrees of left ventricular hypertrophy, usually diffuse, predominantly involving the interventricular septum. The asymptomatic forms with mild or no segmental hypertrophy makes it difficult to establish the diagnosis and screening for familial forms. Its high penetrance is often incomplete and, as a result, 20% to 30% of adults who carry disease-causing gene mutations do not express the phenotype. The susceptibility to sudden death and likelihood of late expression makes establishing a preclinical diagnosis all the more important. The use of Doppler echocardiography and magnetic resonance imaging, in conjunction with a detailed ECG analysis, may be useful in this process. Molecular genetic studies can identify mutations in 60% to 80% of the cases. However, its complex, time-consuming and costly nature, coupled with an inadequate assessment of genotype-phenotype relationships, limits its routine application. Major advances in imaging methods and the introduction of more simplified molecular techniques may contribute to clinical and preclinical diagnosis of hypertrophic cardiomyopathy, in addition to allowing implementation of therapeutic strategies to prevent or delay the development of the disease.

Key Words: Cardiomyopathy, hypertrophic/diagnosis; cardiomyopathy, hypertrophic, familial; hypertrophy, left ventricular

Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of chamber dilation and any other cardiovascular or systemic condition capable of producing similar changes¹. The presence of cellular disarray, fibrosis, and myocyte hypertrophy contributes to the development of diastolic dysfunction, myocardial ischemia, and arrhythmias, which are the substrate of the diseases clinical manifestations^2,3.

Since it was first described, more than four decades ago, HCM has been a subject of intense and fruitful investigation⁴. It is the most prevalent genetic cardiovascular disease, affecting one in every 500 individuals⁵. This is a familial disease with predominantly autosomal dominant pattern of inheritance⁶. More than 400 mutations in genes encoding sarcomeric proteins have already been identified^6,7 (Table 1). Mutations in the β-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3) genes seem to account for 60% to 80% of the cases⁶.

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The great molecular, pathological, and clinical heterogeneity of HCM complicates its diagnosis. Clinical diagnosis is based on predominantly asymmetric LVH associated with normal or reduced cavity on two-dimensional Doppler echocardiography or magnetic resonance imaging^1-3. Atypical forms with mild, localized or nondetectable LVH are usually challenging, making screening for affected individuals more difficult in families known to carry the disease.

Hypertrophic cardiomyopathy is the most common cause of sudden death in young people and athletes, including asymptomatic patients without prior diagnosis or signs of LVH^2,3. The susceptibility to devastating complications, such as sudden death, and progression to disabling conditions, such as heart failure, have prompted a search for indicators capable of identifying the disease at earlier stages. The advent of molecular genetic diagnosis has significantly contributed to the detection of gene mutation carriers without evidence of disease. Because of the incomplete phenotypic penetrance of HCM, Doppler echocardiography fails to detect LVH in 20% to 30% of the genetically affected adult patients^6,8,9. These individuals may show premature predisposition to sudden death or develop the phenotype later in life, as it is the case with mutations in troponin T and cardiac myosin-binding protein-C genes, respectively^10,11. Improvements in imaging methods for assessing left ventricular function and larger scale use of molecular genetic diagnosis may contribute substantially to the identification of the disease in its clinical and preclinical phases.

Clinical features

Hypertrophic cardiomyopathy affects both genders, occurring in patients of different racial backgrounds and in multiple geographic areas³. It usually develops during adolescence, although its clinical manifestations may appear earlier or later, after the fifth decade of life¹². Typically, HCM occurs between the ages 13 and 17 in carriers of HCM-causing gene mutations. Morphological features are usually complete at the age of 18, and there is no progression of left ventricular hypertrophy after this age¹³. The elderly represent 25% of the cases, of which 40% to 50% have obstructive forms of hypertrophic cardiomyopathy¹⁴.

Occasionally, LVH can be present in neonates and children. In infants, it is associated with heart failure and high mortality rates¹⁴. Differential diagnosis should include neuromuscular and metabolic syndromes, which can simulate HCM, such as Friedreichs ataxia, mitochondrial myopathies, incomplete expressions of Noonan and LEOPARD syndromes, and infants born to diabetic mothers³. In families affected by the disease, it is possible to identify children between 4 and 12 years of age with thickened left ventricular (LV) walls. These may or may not correspond to malignant forms, with greater potential for disease progression and early tendency to sudden death¹².

HCM phenotypic penetrance is usually high, but it is age- and gene-dependent⁶. The development of HCM may be observed in adults harboring the mutant gene, between the ages of 30 and 60^11,15. The presence of symptoms and LV outflow tract obstruction is not frequent among these individuals¹². The prognostic significance of these conditions remains unclear, despite a marked susceptibility to sudden death and progression to heart failure^11,12.

The diagnosis of HCM should be suspected in the presence of symptoms, heart murmurs and ECG abnormalities, or even by family screening. At least 50% of the cases are familial^2,6. Diagnostic criteria for familial and nonfamilial HCM in its clinical phase overlap. The absence of family history does not rule out a genetic etiology. It is a disease of incomplete phenotypic penetrance, and de novo mutations can be transmitted to offspring^12,16. Minimal changes in electrocardiogram and imaging modalities are adopted as criteria for preclinical diagnosis of adults with familial HCM (table 2)⁸.

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Most patients are mildly symptomatic or completely asymptomatic. Others have severe limitation and progress to heart failure or die prematurely. Sudden death is reported in 50% to 70% of the patients, especially adolescents and adults younger than 35 years of age, although it may occur at any age¹⁷. The annual incidence of HCM is approximately 1% in adults¹⁸ and 4% in children¹⁹. Cellular disarray and reparative fibrosis, together with LV outflow tract obstruction, microcirculatory disease, and physical exercise, produce electrophysiological instability and favor the genesis of fatal arrhythmias, either as a primary disorder or secondary to myocardial ischemia^2,14,20. In young people and in cardiac troponin T gene mutations, with greater predisposition to premature sudden death, cell disarray and myocardial ischemia are regarded as determinants in the development of fatal arrhythmias¹⁰. In other gene mutations, the degree of fibrosis is related to nonsustained ventricular tachycardia, being an important arrhythmogenic substrate^10,21.

Electrocardiogram

The electrocardiogram is abnormal in 75% to 95% of the patients¹⁴. These changes are seen early, even before adolescence, when Doppler echocardiogram is usually normal²². In adult-onset hypertrophic cardiomyopathy, ECG abnormalities may precede the appearance of LV hypertrophy¹⁵. The following are considered major electrocardiographic diagnostic criteria: left ventricular overload, deep Q-waves > 40 ms in the LV inferolateral wall, and T-wave inversion > 3mm in V3-V6, D1 and aVl and > 5mm in D2, D3 and aVf⁸. Giant negative T-waves in precordial leads are typical of apical HCM. Left ventricular overload occurs in 50% of the cases²². There is no relationship between location and distribution of hypertrophy and the electrocardiographic pattern; likewise, the presence of pathologic Q-waves does not express septal thickness²². Initial slurring of the QRS complex associated with a short PR interval may be indicative of Wolff-Parkinson-White syndrome³.

Electrocardiogram is a valuable tool for screening asymptomatic carriers of the disease without echocardiographic abnormalities in affected families¹⁵. Electrocardiographic changes are seen in 20% to 50% of these cases and should be appropriately evaluated, particularly during preadolescence^8,15. Assessment of carriers of HCM-causing mutant genes without LVH on conventional Doppler echocardiogram shows that the presence of a single major electrocardiographic criterion should be interpreted as diagnostic, considering its low prevalence in the general population⁸. On the other hand, it must be kept in mind that minor electrocardiographic criteria, such as interventricular conduction disturbances, minor changes in ventricular repolarization, and deep S-waves in lead V2, may occasionally occur in the absence of heart disease⁸.

Holter ECG monitoring shows rhythm disturbances in 90% of the adults affected by the disease². Ventricular extrasystoles and nonsustained ventricular tachycardia are found in 20% to 30% of the patients^23,24. Bradyarrhythmias, supraventricular tachycardias, and atrial fibrillation may precede the development of ventricular tachycardia². Repetitive, prolonged episodes of nonsustained ventricular tachycardia predispose to ventricular fibrillation, particularly in patients younger than 30²⁵. Ventricular arrhythmias are rarely seen in children, adolescents and young adults, but when present they have a higher positive predictive value for sudden death²⁶. Sustained ventricular tachycardia may indicate association with LV apical aneurysms or ischemic heart disease³.

Doppler echocardiogram

Doppler echocardiogram plays a decisive role in the diagnosis of HCM, since it identifies major structural and functional changes typical of the disease, as well as a wide phenotypic diversity. Left ventricular hypertrophy ranges from mild to severe, and from localized to diffuse. No morphological pattern of LVH is regarded as truly typical, although asymmetric forms with predominant involvement of the interventricular septum and diffuse hypertrophy are the most frequent¹⁴. Concentric forms represent 1% to 5% of the cases^27,28. Less typically, hypertrophy can be confined to a single ventricular segment, such as the posterior portion of the septum or the anterolateral and posterior free walls, or even LV apical regions²⁷.

The extent and pattern of LVH are inversely correlated with age, and are not associated with gender and functional class¹⁴. Adolescents and young adults often have extreme hypertrophy, with LV wall thickness > 30 mm, which predisposes to sudden death²⁹. Measurements ranging from 15 to 30 mm are common, revealing different degrees of myocardial involvement¹⁴. Borderline thicknesses < 15 mm denote an incipient process and should be differentiated from physiological states, such as athletes heart^2,9,14.

Any value for LV wall thickness may be identified in the presence of a mutant gene, even those regarded as normal^1,8,12. Consequently, screening of families affected by HCM based on LV maximal wall thickness is obviously limited, particularly during childhood and preadolescence. In a recent study, an echocardiographic score calculated as the sum of wall thicknesses obtained in four different LV segments has been shown to be more accurate, especially among younger people³⁰. Left ventricular wall thicknesses of 12 mm in the anterior septum or posterior wall or 14 mm in the posterior septum or free wall are regarded as criterion for the preclinical diagnosis of adult familial forms, when associated with moderate mitral valve systolic anterior motion (SAM) or redundant valve leaflets⁸.

There is a potential relationship between the degree of LVH and the responsible gene. Mutations in the gene encoding the β-myosin heavy chain are associated with diffuse, severe disease³¹. In troponin T mutations, hypertrophy is usually mild or absent¹⁰. Hypertrophic cardiomyopathy caused by myosin-binding protein C gene mutations is associated with normal LV wall thickness at a younger age¹¹.

Doppler echocardiogram allows a distinction to be made between obstructive and non-obstructive forms of HCM. Obstruction affects more often LV outflow tract, due to the anterior or posterior mitral valve leaflet making contact with the basal portions of the interventricular septum^3,14. Mitral valve deformities may contribute to a subaortic gradient. In 45% of the cases of obstructive HCM, the anterior mitral leaflet is elongated or has an anomalous insertion directly into the papillary muscle²⁷. The systolic anterior motion (SAM) of the mitral valve, partly attributed to the Venturi effect, may lead to valvular regurgitation, with the regurgitant jet directed posteriorly¹⁴. Less frequently, there is mid-ventricular obstruction due to excessive papillary muscle hypertrophy and malalignment²⁷.

The degree of obstruction, assessed by continuous Doppler, is dynamic, changing in response to several stimuli and in serial measurements. The gradient changes spontaneously in a same individual, being influenced by intravascular volume, contractility, and afterload^2,32. Provocative maneuvers lack standardization and include Valsalva, amyl nitrite inhalation, post-extrasystole potentiation, dobutamine infusion, and exercise^2,28. A recent study, in which patients without subaortic obstruction under rest conditions were assessed by exercise Doppler echocardiography, has shown predominance of obstructive HCM, corresponding to 70% of the patients³³. The presence of LV outflow tract obstruction is regarded as an independent predictor of progression to heart failure. The likelihood of death from HCM, heart failure, or stroke is higher in these cases³². While LV outflow tract obstruction was associated with elevated risk of sudden death³⁴, its role as a predisposing factor is not well established yet³².

Conventional assessment of global LV systolic function, based on estimated ejection fraction, shows normal or elevated values^3,28. It does not exclude contractile dysfunction, which is better documented by tissue Doppler and strain/strain rate imaging. Left ventricular enlargement with decreased ejection fraction and wall thinning occurs in 5% to 10% of patients who reach maturity^13,35. Assessment of diastolic filling using transmitral Doppler shows abnormal LV relaxation, even though restrictive or pseudonormal filling patterns are also found³.

Tissue Doppler

Tissue Doppler echocardiography is more sensitive than standard Doppler echocardiography for detecting minor changes in left ventricular function^28,36. In patients with overt hypertrophic cardiomyopathy, it can detect left ventricular functional impairment with systolic velocities (S) lower than that obtained in normal controls³⁷. Long-axis diastolic dysfunction is observed by delayed and reduced early (E) and late (A) velocities, as well as prolonged regional deceleration and isovolumic relaxation times³⁸.

The E/E ratio, which can reflect increased LV filling pressure, predicts the degree of exercise tolerance³⁹. There is a correlation between septal E, functional class, and plasma levels of B-type natriuretic peptide (BNP)⁴⁰.

Tissue Doppler imaging permits the detection of changes indicative of left intraventricular asynchrony. Prolonged intraventricular systolic delay indicates predisposition to ventricular tachycardia⁴¹.

Tissue Doppler may be useful in the differential diagnosis between hypertrophic cardiomyopathy and athletes heart. Heterogeneous and reduced systolic and diastolic velocities with asynchrony of contraction are not seen in physiologic states, in which LF function is normal or supernormal³⁶.

This method also enables identification of preclinical HCM^42-44. Systolic (Sa) and early diastolic (Ea) velocities measured by tissue Doppler were reported to be lower in mutation carriers without LVH than in age-matched normal controls⁴². The subsequent development of LVH in serial echocardiography demonstrates that tissue Doppler is effective in identifying genetically affected patients who are more likely to express the HCM phenotype⁴⁵. Despite the promising results obtained so far, only systematic studies involving a larger number of families may define the true role of tissue Doppler as a predictor of LVH development. Just as the disease may not manifest itself later in life because of the incomplete penetrance, minor changes in left ventricular function may not be detected by tissue Doppler²⁸.

Strain and strain rate

More sensitive echocardiographic techniques for characterizing LV structure and function include measurement of the extent and rate of segmental myocardial deformation using strain and strain rate imaging⁴⁶. Midseptal longitudinal strain is decreased in HMC patients, the same being true for the basal portions of the septum and mid-lateral wall, compared with normal controls⁴⁷. Two-dimensional strain analysis shows a decrease in all strain components: longitudinal, radial, circumferential, and transverse⁴⁸.

Strain/strain rate measurement may be useful in the diagnosis of left ventricular dysfunction both in HCM individuals and mutation carriers (phenotype-negative)⁴⁶. Larger studies are needed to assess its effectiveness in detecting HCM at a preclinical stage.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) provides information on LV morphology and performance, including ventricular mass and volumes, in addition to global and regional diastolic and systolic function. Flow dynamics in the LV outflow tract and the degree of mitral regurgitation can also be determined^28,49. It also shows the extent and distribution of myocardial hypertrophy, especially when it is limited to a single LV segment^50-52. This imaging modality is clearly superior to Doppler echocardiography for diagnosing LV apical hypertrophy⁵³, as well as hypertrophy localized in the anterolateral LV free wall, for which ultrasound has shown less diagnostic accuracy⁵¹. In patients with massive LVH, magnetic resonance offers higher resolution than Doppler echocardiography in assessing maximal wall thickness⁵¹. Despite its undeniable role in the identification of phenotypic variants of HCM, it does not replace Doppler echocardiography in the morphological assessment of all patients with HCM^49,51.

Magnetic resonance may establish the differential diagnosis with athletes heart by determining the geometric index, which is calculated as maximal LV end-diastolic wall thickness to LV end-diastolic volume index ratio⁵⁴. It can also differentiate between concentric hypertrophy cardiomyopathy and infiltrative myocardial diseases, such as amyloidosis, characterized by an increase in interatrial septal thickness, as well as in right atrial and right ventricular free wall thickness⁵⁵.

Left ventricular segmental function is assessed by measurement of systolic wall thickening and circumferential strain. Reduced circumferential shortening associated with an abnormal strain pattern is found in hypertrophied segments²⁸. Left ventricular diastolic function measured by contrast-enhanced magnetic resonance may be used to assess HCM, but warrants additional studies.

The histopathological substrate of the disease can be analyzed by gadolinium-enhanced MRI. Late enhancement is found in 80% of the patients, involving 0 to 48% of myocardial mass with different patterns of distribution^56,57. It is directly related to areas of reparative fibrosis, in which collagen is the predominant component⁵⁸. Two patterns of distribution are described: diffuse and confluent⁵⁶. Late enhancement has prognostic value in HCM. Its extent is associated with greater predisposition to sudden death and progressive left ventricular dilation. The diffuse pattern, more than the confluent, is associated with the presence of at least two risk factors for sudden death⁵⁶. When multifocal, it is correlated with a greater degree of fibrosis and decreased ejection fraction⁵⁹. Areas of late enhancement were not detected in mutation carriers without the HCM phenotype, suggesting that fibrosis only develops after appearance of LV hypertrophy⁵⁷. In 81% of the phenotype-negative subjects, MRI revealed the presence of triangular, deep, bright structural abnormalities in the basal and mid segments of the LV inferoseptal wall⁶⁰. The depth of these images decreased with increased wall thickness, which may explain the absence of such a description in histopathological studies, usually restricted to forms with complete phenotypic expression. Gadolinium-enhanced MRI may facilitate the differential diagnosis with Fabry disease, which accounts for 4% of patients diagnosed with HCM⁶¹.

Phosphorus-31 nuclear magnetic resonance spectroscopy may be potentially used in the preclinical diagnosis of HCM. The cardiac phosphocreatine-to-ATP ratio, which can reflect abnormalities in myocardial metabolism, is 30% lower in HCM patients, even in the absence of LVH, despite the overlapping results with the normal control group⁶².

Endomyocardial biopsy

Endomyocardial biopsy is performed to identify the histopathological substrate of the disease, the less specific feature and focal distribution of which limit its use in routine screening for HCM. More recently, studies based on necropsy or in explanted hearts have analyzed the interrelation between several histopathological components and their respective association with clinical outcomes^10,21,63,64.

Endomyocardial biopsy, using light microscopy, shows various degrees of cellular hypertrophy and fibrosis. On electron microscopy, morphological changes are usually nonspecific⁶⁵. Cellular disarray, lying deep within the interventricular septum, is often beyond the reach of the bioptome⁶⁵, occupying approximately 30% of the left ventricular wall¹⁴. It is not pathognomonic, affecting, in a localized form, subjects with normal hearts or with congenital heart diseases. Its extension is inversely related to age⁶³. Cellular disarray is not associated with specific LVH patterns, but is more diffuse in the presence of maximal wall thickness < 20 mm, preserved systolic function, and young patients with sudden premature death^21,63.

Interstitial or reparative fibrosis may be focal or occupy extensive areas of the myocardium, and it is directly related to age, maximal LV wall thickness, and the presence of a dilated chamber⁶³. Fibrosis is more severe in patients who progress to sudden death at a more advanced age²¹.

Microcirculation impairment is characterized by wall thickening due to myointimal hyperplasia and the ensuing luminal narrowing of small intramural arteries, being more pronounced in the interventricular septum⁶⁵. It is implicated in the development of reparative fibrosis and progression to dilated hypertrophic cardiomyopathy¹⁴. This is an early finding that affects even the very young⁶³.

Endomyocardial biopsy may be used for the differential diagnosis with LVH of other etiologies, interventricular septal tumors, and infiltrative diseases, such as cardiac amyloidosis. Myocardial infiltrative processes may be clinically indistinguishable from HCM, such as Pompe disease, which affects children¹. In Fabry disease, an X-linked recessive lysosomal disorder, potentially treatable, deficiency of α-galactosidase A is associated with glycosphingolipid deposition in the myocardium in older men⁶⁶. Mutations in genes related to cell metabolism, described recently, mimic familial hypertrophic cardiomyopathy. Mutations in the gene encoding the β² regulatory subunit of the AMP-activated protein kinase (PRKAG2) cause storage disease, in which Wolff-Parkinson-White syndrome and premature conduction disease are associated with varying degrees of pseudo ventricular hypertrophy⁶⁷. Mutations in the lysosome-associated membrane protein-2 (LAMP2) result in Danon disease, with massive myocardial hypertrophy accompanied by Wolff-Parkinson-White syndrome⁶⁸. In both diseases, histopathological examination reveals lack of cellular disarray and presence of glycogen-containing vacuoles.

Electrophysiological studies

The role of electrophysiological studies (EPS) using programmed ventricular stimulation to assess the arrhythmogenic substrate of HCM has not yet been established. Although some relationship has been demonstrated between inducibility and prognosis, its predictive accuracy is debatable^2,14,20. It may be helpful in patients with unexplained syncope². High resolution ECG has low predictive accuracy as well²⁰. T-wave alternans is regarded as predictive of ventricular arrhythmias and sudden death. Its contribution to risk stratification in HCM may be limited and needs further evaluation⁶⁹.

Molecular genetic diagnosis

DNA analysis is the most definitive method for identifying HCM in its clinical and preclinical phases. The heterogeneous molecular substrate, represented by hundreds of mutations in multiple genes, adds complexity to the genetic diagnosis and limits its use in routine clinical practice. Because of the marked allelic heterogeneity, together with low individual prevalence of mutations, it is difficult to assess the genotype-phenotype relationship. The significant inter- and intrafamilial phenotypic variability is attributed to the action of modifying agents, either environmental or genetic, and to the likelihood of occurring more than one mutation in one or more genes^6,16.

Molecular genetic diagnosis is a valuable tool for assessing familial forms of the disease, particularly those associated with sudden death or late clinical expression^2,6,7. It enables the early release of normal family members and follow-up of those who carry mutations but have no evidence of the disease. Prospective studies are needed to determine whether these individuals will necessarily express the phenotype. Preclinical diagnosis may produce adverse psychological effects, particularly in children and adolescents. In this regard, multidisciplinary genetic counseling is considered mandatory.

Molecular genetic diagnosis helps differentiate other forms of LVH and phenocopies, including metabolic storage diseases, which are clinically indistinguishable from HCM^66-68.

The use of genetic analysis in risk stratification for sudden death is supported by descriptions of malignant mutations. Early studies based on large pedigrees relate certain phenotypes to the mutant genes and discriminate between mutations with good and poor prognosis^7,10,11. More recent studies provided new data on HCM clinical and genetic profile, revealing less specific phenotypes and lower prevalence of malignant mutations^31,70,71. For the purpose of prognostic evaluation, it is necessary to expand the analysis of genotype-phenotype relationships, including larger, unrelated families with a higher number of affected members^7,20.

As molecular genetic diagnosis is expensive and time-consuming, it has been limited to research centers. Single-strand conformation polymorphisms (SSCP) analysis can map 60% to 80% of the cases⁶. The advent of automated, direct DNA sequencing contributes to its use on a clinical scale, since it allows rapid screening for up to eight sarcomeric genes, but is still expensive^7,12.The likelihood of false-negatives due to mutations in genes that were not assessed does exist.

Molecular genetic diagnosis should prompt implementation of measures designed to prevent or delay disease progression, such as gene therapy. The multitude of structural and functional disorders involving contractile proteins has been a drawback to the development of effective therapeutic strategies.

Conclusion

Hypertrophic cardiomyopathy is a disease with a heterogeneous molecular genetic substrate and significant phenotypic variability, which makes clinical and preclinical diagnosis very complex. Higher resolution imaging modalities and affordable molecular techniques will allow early diagnosis and implementation of measures that may prevent the development of LVH and progression to sudden death.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any graduation program.

References

1. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, et al. American Heart Association Scientific Statement. Contemporary definitions and classification of the cardiomyopathies. Circulation. 2006; 113 (14): 1807-16.
2. Maron BJ, McKenna WJ, Danielson G, Kappenberger LJ, Kuhn HJ, Seidman CE, et al. American College of Cardiology/ European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. Eur Heart J. 2003; 24: 1965-90.
3. Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet. 2004; 363: 1881-91.
4. Teare D. Assymetrical hypertrophy of the heart. Br Heart J. 1958; 20: 1-8.
5. Maron BJ, Gardner JM, Flack JM, Gidding SS, Kurosaki TT, Bild DF. Prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiographic analysis of 4111 subjects in the CARDIA study. Circulation. 1995; 92: 785-9.
6. Richard P, Villard E, Charron P, Isnard R. The genetic bases of cardiomyopathies. J Am Coll Cardiol. 2006; 48: A79-89.
7. Ashrafian H, Watkins H. Reviews of translational medicine and genomics in cardiovascular disease: new disease taxonomy and therapeutics implications. Cardiomyopathies: therapeutics based on molecular phenotype. J Am Coll Cardiol. 2007; 49: 1251-64.
8. McKenna WJ, Spirito P, Desnos M, Dubourg O, Komadja M. Experience of clinical genetics in hypertrophic cardiomyopathy: proposal for new diagnostic criteria in adults members of affected families. Heart. 1997; 77: 130-2.
9. Hagège AA, Dubourg O, Desnos M, Mirochnik R, Isnard G, Bonne G, et al. Familial hypertrophic cardiomyopathy: cardiac ultrasonic abnormalities in genetically affected subjects without echocardiographic evidence of left ventricular hypertrophy. Eur Heart J. 1998; 19: 490-9.
10. Varnava AM, Elliott PM, Baboonian C, Davison F, Davies MJ, McKenna WJ. Hypertrophic cardiomyopathy: histopathological features of sudden death in cardiac troponin T disease. Circulation. 2001; 104: 1308-4.
11. Maron BJ, Niimura H, Casey SA, Soper MK, Wright GB, Seidman JG, et al. Development of ventricular hypertrophy in adults with hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C mutations. J Am Coll Cardiol. 2001; 38: 315-21.
12. Maron BJ, Seidman JG, Seidman CE. Proposal for contemporary strategies in families with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004; 44: 2125-32.
13. Spirito P, Maron BJ. Absence of progression of left ventricular hypertrophy in adult patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 1987; 9: 1013-7.
14. Maron BJ. Hypertrophic cardiomyopathy - a systematic review. JAMA. 2002; 287: 1308-20.
15. Charron P, Dubourg O, Desnos M, Isnard R, Hagege A, Millaire A, et al. . Diagnostic value of eletrocardiography and echocardiography for familial hypertrophic cardiomyopathy in a genotyped adult population. Circulation. 1997; 96: 214-9.
16. Seidman JG, Seidman C. The genetic basis for cardiomyopathies: from mutation identification to mechanistic paradigms. Cell. 2001; 54: 557-67.
17. Maron BJ, Olivotto I, Spirito P, Casey SA, Bellone P, Gohman TE, et al. Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral based patient population. Circulation. 2000; 102: 858-64.
18. Arteaga E, Ianni BM, Fernandes F, Mady C. Benign outcome in a long-term follow-up of patients with hypertrophic cardiomyopathy in Brazil. Am Heart J. 2005; 149: 1099-105.
19. McKenna WJ, Deanfield J, Faruqui A, England D, Oakley C, Goodwin JF. Prognosis in hypertrophic cardiomyopathy: role of age, clinical, electrocardiographic, and haemodynamic features. Am J Cardiol. 1981; 47: 532-8.
20. Mattos BP. Estratificação de risco para morte súbita na cardiomiopatia hipertrófica: bases genéticas e clínicas. Arq Bras Cardiol. 2006; 87: 391-9.
21. Varnava A, Elliott PM, Mahon N, Davies MJ, McKenna WJ. Relation between myocyte disarray and outcome in hypertrophic cardiomyopathy. Am J Cardiol. 2001; 88: 275-9.
22. Maron BJ. The electrocardiogram as a diagnostic tool for hypertrophic cardiomyopathy: revisited. Ann Noninvas Electrocardiol. 2001; 6: 277-9.
23. 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: 697-704.
24. Medeiros PT, Martinelli Fş N, Arteaga E, Costa R, Siqueira S, Mady C, et al. Cardiomiopatia hipertrófica: importância dos eventos arrítmicos em pacientes com risco de morte súbita. Arq Bras Cardiol. 2006; 87: 649-57.
25. Montserrat 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: 873-9.
26. McKenna WJ, Behr ER. Hypertrophic cardiomyopathy: management, risk stratification and prevention of sudden death. Heart. 2002; 87: 169-76.
27. Klues HGL, Schiffers A, Maron BJ. Phenotypic spectrum of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients. J Am Coll Cardiol. 1995; 26: 1699-708.
28. Nagueh SF, Mahmarian JJ. Non-invasive cardiac imaging in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2006; 48: 2410-22.
29. Maron BJ, Piccinimmo M, Casey SA, Bernabo P, Spirito P. Relation of extreme left ventricular hypertrophy with survival to advanced age in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2003; 42: 882-8.
30. Forissier JF, Charron P, Tezenas du Montcel S, Hagege A, Isnard R, Carrier L, et al. Diagnostic accuracy of a 2 D left ventricle hypertrophy score for familial hypertrophic cardiomyopathy. Eur Heart J. 2005, 26: 1882-6.
31. Van Driest SL, Jarger MA, Ommen SR, Will ML, Gersh BJ, Tajik AJ, et al. Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004; 44: 602-10.
32. Maron BJ, Olivotto I, Maron MS. The dilemma of left ventricular outflow tract obstruction and sudden death in hypertrophic cardiomyopathy: do patients with gradients really deserve prophylactic defibrillators? Eur Heart J. 2006; 27: 1895-7.
33. Maron BJ, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006; 114: 2232-9.
34. Elliott PM, Gimeno JR, Tomé MT, McKenna W. Left ventricular outflow tract obstruction and sudden death risk in hypertrophic cardiomyopathy. Eur Heart J. 2006; 27: 1933-41.
35. Thaman R, Gimeno JR, Murphy RT, Kubo T, Sachdev B, Mogensen J, et al. Prevalence and clinical significance of systolic impairment in hypertrophic cardiomyopathy. Heart. 2005; 91: 920-5.
36. Rajiv C, Vinereanu D, Fraser AG. Tissue Doppler imaging for the evaluation of patients with hypertrophic cardiomyopathy. Curr Opin Cardiol. 2004; 19: 430-6.
37. Vinereanu D, Florescu N, Sculthorpe N, Tweddel AC, Stephens MR, Fraser AG. Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol. 2001; 88: 53-8.
38. Severino S, Caso P, Galderisi M, De Simone L, Petrocelli A, de Divitiis O, et al. Use of pulsed tissue imaging to assess regional left ventricular diastolic dysfunction in hypertrophic cardiomyopathy. Am J Cardiol. 1998; 82: 1394-8.
39. Matsumara Y, Elliott PM, Virdee MS, Sorajja P, Doi Y, McKenna WJ. Left ventricular diastolic function assessing using Doppler tissue imaging in patients with hypertrophic cardiomyopathy: relation to symptoms and exercise capacity. Heart. 2002; 87:247-51.
40. Karia DH, Harris KM, Zenovich AG, Maron BJ. Tissue Doppler image predicts NYHA functional class and plasma BNP levels in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2006; 47 (Suppl A): 1167.
41. D'Andrea A, Caso P, Severino S, Cuomo S, Capozzi G, Calabrio P, et al. Prognostic value of intra left ventricular electromechanical asynchrony in patients with hypertrophic cardiomyopathy. Eur Heart J. 2006; 27: 1311-8.
42. Nagueh S, Bachinski LL, Meyer D, Hill R, Zoghbi WA, Tam JW, et al. Tissue Doppler imaging detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for early diagnosis before and independently of hypertrophy. Circulation. 2001; 104: 128-30.
43. Ho C, Sweiter NK, McDonough B, Maron BJ, Casey SA, Seidman JG, et al. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation. 2002; 105: 2992-7.
44. Cardim N, Perrot A, Ferreira T, Pereira A, Osterziel KJ, Reis RP, et al. Usefulness of Doppler myocardial imaging for identification of mutation carriers of familial hypertrophic cardiomyopathy. Am J Cardiol. 2002; 90: 128-32.
45. Nagueh S, McFalls J, Meyer D, Hill R, Zoghbi WA, Tam JW, et al. Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease. Circulation. 2003; 108: 395-8.
46. Marwick TH. Measurement of strain and strain rate by echocardiography. J Am Coll Cardiol. 2006; 47: 1313-27.
47. Yang H, Sum JP, Lever HM, Popovic ZB, Drinko JK, Greenberg NL, et al. Use of strain imaging in detecting segmental dysfunction in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr. 2003; 16: 233-9.
48. Serri K, Reant P, Lafitte M, Berhouet M, Le Bouffos V, Roudaut R, et al. Global and regional myocardial function quantification by two-dimensional strain: application in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2006; 47: 1175-81.
49. Pennell DJ, Sechten UP, Higgins CB, Manning WJ, Pohost GM, Rademakers FE, et al. Working group of cardiovascular magnetic resonance of the European Society of Cardiology. Clinical indications for cardiovascular magnetic resonance. Eur Heart J. 2004; 25: 1940-65.
50. Budoff MJ, Cohen MC, Garcia MJ, Hodgson JM, Hundley WG, Lima JA. American Heart Association clinical competence statement on cardiac imaging with computed tomography and magnetic resonance. J Am Coll Cardiol. 2005; 46: 383-402.
51. Rickers C, Wilke N, Jarosch-Herold M, Casey SA, Panse P, Panse N, et al. Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation. 2005; 112: 855-66.
52. Shiozaki AA, Kim RJ, Parga JR, Tassi EM, Arteaga E, Rochitte CE. Ressonância magnética cardiovascular na cardiomiopatia hipertrófica. Arq Bras Cardiol. 2007; 88: 243-8.
53. Moon JCC, Fisher NG, McKenna WJ, Penell DJ. Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography. Heart. 2004; 90: 645-9.
54. Petersen SE, Selvanyagam JB, Francis JM, Myerson SG, Wilsmann F, Robson MD. Differentation of athlete's heart from pathological forms of cardiac hypertrophy by means of geometric indices derived from cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2005; 7: 551-8.
55. Fattori R, Rocchi G, Celetti F, Bertaccini P, Rapezzi C, Gavelli G. Contribution of magnetic resonance imaging in the diffential diagnosis of cardiac amyloidosis and symmetric hypertrophic cardiomyopathy. Am Heart J. 1998; 136: 824-30.
56. Moon JCC, McKenna WJ, McKrohon JA, Elliott PM, Penell DJ. Toward risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance . J Am Coll Cardiol. 2003; 41: 1561-7.
57. Moon JCC, Mogensen J, Elliott PM, Smith GC, Elkington AG, Prasad SK, et al. Myocardial late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy caused by mutations in troponin I. Heart. 2005; 91: 1036-40.
58. Moon JC, Reed E, Sheppard MA, Elkington AG, Ho SY, Burke M, et al. The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004; 43: 2260-4.
59. Shiozaki AA, Santos TS, Arteaga E, Parga JR, Avila LF, Mady C, et al. The amount and pattern of myocardial fibrosis correlate to left ventricular dysfunction in hypertrophic cardiomyopathy patients by cardiovascular magnetic resonance. J Am Coll Cardiol. 2007; 49 (Suppl A): 118A.
60. Germans T, Wilde AAM, Dijkmans PA, Chai W, Kamp O, Pinto YM, et al. Structural abnormalities of the inferoseptal left ventricular wall tested by cardiac magnetic resonance imaging in carriers of hypertrophic cardiomyopathy mutations. J Am Coll Cardiol. 2006; 48: 2518-23.
61. Moon JCC, Sachder B, Elkington AG, McKenna WJ, Metha A, Pennell DJ, et al. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease: evidence for a disease specific abnormality of the myocardial interstitum. Eur Heart J. 2003; 24: 2151-5.
62. Crilley JG, Boehm EA, Blair E, Rajagopalan B, Blamire AM, Styles P, et al. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll Cardiol. 2003; 41: 1776-82.
63. Varnava AM, Elliott PM, Sharma S, McKenna WJ, Davies MJ. Hypertrophic cardiomyopathy: the interrelation between disarray, fibrosis and small vessel disease. Heart. 2000; 84: 476-82.
64. Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A. Hypertrophic cardiomyopathy and sudden death in the young: pathological incidence of myocardial ischemia. Hum Pathol. 2000; 31: 988-98.
65. Hauck AD, Edwards WD. Histopathologic examination of tissue obtained by endomyocardial biopsy. In: Fowles RE. Cardiac biopsy. Mount Kisco: Futura Publishing CO; 1992. p. 95-153.
66. Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, et al. Prevalence of Anderson-Fabry disease in male patients with late-onset hypertrophic cardiomyopathy. Circulation. 2002; 105: 1407-11.
67. Murphy RT, Mogensen J, McGerry K, Bahl A, Evans A, Osman E, et al. Adenosine-monophosphate-activated-protein kinase disease mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome. J Am Coll Cardiol. 2005; 45: 922-30.
68. Charron P, Villard P, Sebillon P, Laforêt P, Maisonobe T, Duboscq-Bidot L, et al. Danon's disease as a cause of hypertrophic cardiomyopathy: a systematic survey. Heart. 2004; 90: 842-6.
69. Cuoco FA, Colley BJ, Spencer WH, Burke SW, Sayar SN, Kusmirek SL. Microvolt-T-wave alternans does not predict appropriate implantable defibrillator dischargers or correlate with traditional risk factors for sudden cardiac death in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 2007; 49 (Suppl A): 30A.
70. Tirone A, Arteaga E, Pereira Barreto AC, Krieger JE, Buck PC, Ianni BM, et al. Pesquisa de marcadores para os genes da cadeia pesada da β miosina cardíaca e da proteína C de ligação à miosina em familiares de pacientes com cardiomiopatia hipertrófica. Arq Bras Cardiol. 2005; 84: 467-72.
71. Van Driest SL, Ommen SR, Tajik J, Gersh BJ, Ackerman MJ. Genotyping in hypertrophic cardiomyopathy. Mayo Clin Proc. 2005; 85: 463-9.

Correspondência:

Beatriz Piva e Mattos

Rua Ramiro Barcelos, 2350/2060

90035-903 - Porto Alegre, RS - Brasil

E-mail:

bpmattos@cardiol.br

Publication Dates

Publication in this collection
25 July 2008
Date of issue
July 2008

History

Reviewed
23 Nov 2007
Received
26 Apr 2007
Accepted
10 Jan 2008

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, et al. American Heart Association Scientific Statement. Contemporary definitions and classification of the cardiomyopathies. Circulation. 2006; 113 (14): 1807-16.

[2] 2. Maron BJ, McKenna WJ, Danielson G, Kappenberger LJ, Kuhn HJ, Seidman CE, et al. American College of Cardiology/ European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. Eur Heart J. 2003; 24: 1965-90.

[3] 3. Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet. 2004; 363: 1881-91.

[4] 4. Teare D. Assymetrical hypertrophy of the heart. Br Heart J. 1958; 20: 1-8.

[5] 5. Maron BJ, Gardner JM, Flack JM, Gidding SS, Kurosaki TT, Bild DF. Prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiographic analysis of 4111 subjects in the CARDIA study. Circulation. 1995; 92: 785-9.

[6] 6. Richard P, Villard E, Charron P, Isnard R. The genetic bases of cardiomyopathies. J Am Coll Cardiol. 2006; 48: A79-89.

[7] 7. Ashrafian H, Watkins H. Reviews of translational medicine and genomics in cardiovascular disease: new disease taxonomy and therapeutics implications. Cardiomyopathies: therapeutics based on molecular phenotype. J Am Coll Cardiol. 2007; 49: 1251-64.

[8] 8. McKenna WJ, Spirito P, Desnos M, Dubourg O, Komadja M. Experience of clinical genetics in hypertrophic cardiomyopathy: proposal for new diagnostic criteria in adults members of affected families. Heart. 1997; 77: 130-2.

[9] 9. Hagège AA, Dubourg O, Desnos M, Mirochnik R, Isnard G, Bonne G, et al. Familial hypertrophic cardiomyopathy: cardiac ultrasonic abnormalities in genetically affected subjects without echocardiographic evidence of left ventricular hypertrophy. Eur Heart J. 1998; 19: 490-9.

[10] 10. Varnava AM, Elliott PM, Baboonian C, Davison F, Davies MJ, McKenna WJ. Hypertrophic cardiomyopathy: histopathological features of sudden death in cardiac troponin T disease. Circulation. 2001; 104: 1308-4.

[11] 11. Maron BJ, Niimura H, Casey SA, Soper MK, Wright GB, Seidman JG, et al. Development of ventricular hypertrophy in adults with hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C mutations. J Am Coll Cardiol. 2001; 38: 315-21.

[12] 12. Maron BJ, Seidman JG, Seidman CE. Proposal for contemporary strategies in families with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004; 44: 2125-32.

[13] 13. Spirito P, Maron BJ. Absence of progression of left ventricular hypertrophy in adult patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 1987; 9: 1013-7.

[14] 14. Maron BJ. Hypertrophic cardiomyopathy - a systematic review. JAMA. 2002; 287: 1308-20.

[15] 15. Charron P, Dubourg O, Desnos M, Isnard R, Hagege A, Millaire A, et al. . Diagnostic value of eletrocardiography and echocardiography for familial hypertrophic cardiomyopathy in a genotyped adult population. Circulation. 1997; 96: 214-9.

[16] 16. Seidman JG, Seidman C. The genetic basis for cardiomyopathies: from mutation identification to mechanistic paradigms. Cell. 2001; 54: 557-67.

[17] 17. Maron BJ, Olivotto I, Spirito P, Casey SA, Bellone P, Gohman TE, et al. Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral based patient population. Circulation. 2000; 102: 858-64.

[18] 18. Arteaga E, Ianni BM, Fernandes F, Mady C. Benign outcome in a long-term follow-up of patients with hypertrophic cardiomyopathy in Brazil. Am Heart J. 2005; 149: 1099-105.

[19] 19. McKenna WJ, Deanfield J, Faruqui A, England D, Oakley C, Goodwin JF. Prognosis in hypertrophic cardiomyopathy: role of age, clinical, electrocardiographic, and haemodynamic features. Am J Cardiol. 1981; 47: 532-8.

[20] 20. Mattos BP. Estratificação de risco para morte súbita na cardiomiopatia hipertrófica: bases genéticas e clínicas. Arq Bras Cardiol. 2006; 87: 391-9.

[21] 21. Varnava A, Elliott PM, Mahon N, Davies MJ, McKenna WJ. Relation between myocyte disarray and outcome in hypertrophic cardiomyopathy. Am J Cardiol. 2001; 88: 275-9.

[22] 22. Maron BJ. The electrocardiogram as a diagnostic tool for hypertrophic cardiomyopathy: revisited. Ann Noninvas Electrocardiol. 2001; 6: 277-9.

[23] 23. 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: 697-704.

[24] 24. Medeiros PT, Martinelli Fş N, Arteaga E, Costa R, Siqueira S, Mady C, et al. Cardiomiopatia hipertrófica: importância dos eventos arrítmicos em pacientes com risco de morte súbita. Arq Bras Cardiol. 2006; 87: 649-57.

[25] 25. Montserrat 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: 873-9.

[26] 26. McKenna WJ, Behr ER. Hypertrophic cardiomyopathy: management, risk stratification and prevention of sudden death. Heart. 2002; 87: 169-76.

[27] 27. Klues HGL, Schiffers A, Maron BJ. Phenotypic spectrum of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients. J Am Coll Cardiol. 1995; 26: 1699-708.

[28] 28. Nagueh SF, Mahmarian JJ. Non-invasive cardiac imaging in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2006; 48: 2410-22.

[29] 29. Maron BJ, Piccinimmo M, Casey SA, Bernabo P, Spirito P. Relation of extreme left ventricular hypertrophy with survival to advanced age in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2003; 42: 882-8.

[30] 30. Forissier JF, Charron P, Tezenas du Montcel S, Hagege A, Isnard R, Carrier L, et al. Diagnostic accuracy of a 2 D left ventricle hypertrophy score for familial hypertrophic cardiomyopathy. Eur Heart J. 2005, 26: 1882-6.

[31] 31. Van Driest SL, Jarger MA, Ommen SR, Will ML, Gersh BJ, Tajik AJ, et al. Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004; 44: 602-10.

[32] 32. Maron BJ, Olivotto I, Maron MS. The dilemma of left ventricular outflow tract obstruction and sudden death in hypertrophic cardiomyopathy: do patients with gradients really deserve prophylactic defibrillators? Eur Heart J. 2006; 27: 1895-7.

[33] 33. Maron BJ, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006; 114: 2232-9.

[34] 34. Elliott PM, Gimeno JR, Tomé MT, McKenna W. Left ventricular outflow tract obstruction and sudden death risk in hypertrophic cardiomyopathy. Eur Heart J. 2006; 27: 1933-41.

[35] 35. Thaman R, Gimeno JR, Murphy RT, Kubo T, Sachdev B, Mogensen J, et al. Prevalence and clinical significance of systolic impairment in hypertrophic cardiomyopathy. Heart. 2005; 91: 920-5.

[36] 36. Rajiv C, Vinereanu D, Fraser AG. Tissue Doppler imaging for the evaluation of patients with hypertrophic cardiomyopathy. Curr Opin Cardiol. 2004; 19: 430-6.

[37] 37. Vinereanu D, Florescu N, Sculthorpe N, Tweddel AC, Stephens MR, Fraser AG. Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol. 2001; 88: 53-8.

[38] 38. Severino S, Caso P, Galderisi M, De Simone L, Petrocelli A, de Divitiis O, et al. Use of pulsed tissue imaging to assess regional left ventricular diastolic dysfunction in hypertrophic cardiomyopathy. Am J Cardiol. 1998; 82: 1394-8.

[39] 39. Matsumara Y, Elliott PM, Virdee MS, Sorajja P, Doi Y, McKenna WJ. Left ventricular diastolic function assessing using Doppler tissue imaging in patients with hypertrophic cardiomyopathy: relation to symptoms and exercise capacity. Heart. 2002; 87:247-51.

[40] 40. Karia DH, Harris KM, Zenovich AG, Maron BJ. Tissue Doppler image predicts NYHA functional class and plasma BNP levels in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2006; 47 (Suppl A): 1167.

[41] 41. D'Andrea A, Caso P, Severino S, Cuomo S, Capozzi G, Calabrio P, et al. Prognostic value of intra left ventricular electromechanical asynchrony in patients with hypertrophic cardiomyopathy. Eur Heart J. 2006; 27: 1311-8.

[42] 42. Nagueh S, Bachinski LL, Meyer D, Hill R, Zoghbi WA, Tam JW, et al. Tissue Doppler imaging detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for early diagnosis before and independently of hypertrophy. Circulation. 2001; 104: 128-30.

[43] 43. Ho C, Sweiter NK, McDonough B, Maron BJ, Casey SA, Seidman JG, et al. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation. 2002; 105: 2992-7.

[44] 44. Cardim N, Perrot A, Ferreira T, Pereira A, Osterziel KJ, Reis RP, et al. Usefulness of Doppler myocardial imaging for identification of mutation carriers of familial hypertrophic cardiomyopathy. Am J Cardiol. 2002; 90: 128-32.

[45] 45. Nagueh S, McFalls J, Meyer D, Hill R, Zoghbi WA, Tam JW, et al. Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease. Circulation. 2003; 108: 395-8.

[46] 46. Marwick TH. Measurement of strain and strain rate by echocardiography. J Am Coll Cardiol. 2006; 47: 1313-27.

[47] 47. Yang H, Sum JP, Lever HM, Popovic ZB, Drinko JK, Greenberg NL, et al. Use of strain imaging in detecting segmental dysfunction in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr. 2003; 16: 233-9.

[48] 48. Serri K, Reant P, Lafitte M, Berhouet M, Le Bouffos V, Roudaut R, et al. Global and regional myocardial function quantification by two-dimensional strain: application in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2006; 47: 1175-81.

[49] 49. Pennell DJ, Sechten UP, Higgins CB, Manning WJ, Pohost GM, Rademakers FE, et al. Working group of cardiovascular magnetic resonance of the European Society of Cardiology. Clinical indications for cardiovascular magnetic resonance. Eur Heart J. 2004; 25: 1940-65.

[50] 50. Budoff MJ, Cohen MC, Garcia MJ, Hodgson JM, Hundley WG, Lima JA. American Heart Association clinical competence statement on cardiac imaging with computed tomography and magnetic resonance. J Am Coll Cardiol. 2005; 46: 383-402.

[51] 51. Rickers C, Wilke N, Jarosch-Herold M, Casey SA, Panse P, Panse N, et al. Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation. 2005; 112: 855-66.

[52] 52. Shiozaki AA, Kim RJ, Parga JR, Tassi EM, Arteaga E, Rochitte CE. Ressonância magnética cardiovascular na cardiomiopatia hipertrófica. Arq Bras Cardiol. 2007; 88: 243-8.

[53] 53. Moon JCC, Fisher NG, McKenna WJ, Penell DJ. Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography. Heart. 2004; 90: 645-9.

[54] 54. Petersen SE, Selvanyagam JB, Francis JM, Myerson SG, Wilsmann F, Robson MD. Differentation of athlete's heart from pathological forms of cardiac hypertrophy by means of geometric indices derived from cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2005; 7: 551-8.

[55] 55. Fattori R, Rocchi G, Celetti F, Bertaccini P, Rapezzi C, Gavelli G. Contribution of magnetic resonance imaging in the diffential diagnosis of cardiac amyloidosis and symmetric hypertrophic cardiomyopathy. Am Heart J. 1998; 136: 824-30.

[56] 56. Moon JCC, McKenna WJ, McKrohon JA, Elliott PM, Penell DJ. Toward risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance . J Am Coll Cardiol. 2003; 41: 1561-7.

[57] 57. Moon JCC, Mogensen J, Elliott PM, Smith GC, Elkington AG, Prasad SK, et al. Myocardial late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy caused by mutations in troponin I. Heart. 2005; 91: 1036-40.

[58] 58. Moon JC, Reed E, Sheppard MA, Elkington AG, Ho SY, Burke M, et al. The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004; 43: 2260-4.

[59] 59. Shiozaki AA, Santos TS, Arteaga E, Parga JR, Avila LF, Mady C, et al. The amount and pattern of myocardial fibrosis correlate to left ventricular dysfunction in hypertrophic cardiomyopathy patients by cardiovascular magnetic resonance. J Am Coll Cardiol. 2007; 49 (Suppl A): 118A.

[60] 60. Germans T, Wilde AAM, Dijkmans PA, Chai W, Kamp O, Pinto YM, et al. Structural abnormalities of the inferoseptal left ventricular wall tested by cardiac magnetic resonance imaging in carriers of hypertrophic cardiomyopathy mutations. J Am Coll Cardiol. 2006; 48: 2518-23.

[61] 61. Moon JCC, Sachder B, Elkington AG, McKenna WJ, Metha A, Pennell DJ, et al. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease: evidence for a disease specific abnormality of the myocardial interstitum. Eur Heart J. 2003; 24: 2151-5.

[62] 62. Crilley JG, Boehm EA, Blair E, Rajagopalan B, Blamire AM, Styles P, et al. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll Cardiol. 2003; 41: 1776-82.

[63] 63. Varnava AM, Elliott PM, Sharma S, McKenna WJ, Davies MJ. Hypertrophic cardiomyopathy: the interrelation between disarray, fibrosis and small vessel disease. Heart. 2000; 84: 476-82.

[64] 64. Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A. Hypertrophic cardiomyopathy and sudden death in the young: pathological incidence of myocardial ischemia. Hum Pathol. 2000; 31: 988-98.

[65] 65. Hauck AD, Edwards WD. Histopathologic examination of tissue obtained by endomyocardial biopsy. In: Fowles RE. Cardiac biopsy. Mount Kisco: Futura Publishing CO; 1992. p. 95-153.

[66] 66. Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, et al. Prevalence of Anderson-Fabry disease in male patients with late-onset hypertrophic cardiomyopathy. Circulation. 2002; 105: 1407-11.

[67] 67. Murphy RT, Mogensen J, McGerry K, Bahl A, Evans A, Osman E, et al. Adenosine-monophosphate-activated-protein kinase disease mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome. J Am Coll Cardiol. 2005; 45: 922-30.

[68] 68. Charron P, Villard P, Sebillon P, Laforêt P, Maisonobe T, Duboscq-Bidot L, et al. Danon's disease as a cause of hypertrophic cardiomyopathy: a systematic survey. Heart. 2004; 90: 842-6.

[69] 69. Cuoco FA, Colley BJ, Spencer WH, Burke SW, Sayar SN, Kusmirek SL. Microvolt-T-wave alternans does not predict appropriate implantable defibrillator dischargers or correlate with traditional risk factors for sudden cardiac death in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 2007; 49 (Suppl A): 30A.

[70] 70. Tirone A, Arteaga E, Pereira Barreto AC, Krieger JE, Buck PC, Ianni BM, et al. Pesquisa de marcadores para os genes da cadeia pesada da β miosina cardíaca e da proteína C de ligação à miosina em familiares de pacientes com cardiomiopatia hipertrófica. Arq Bras Cardiol. 2005; 84: 467-72.

[71] 71. Van Driest SL, Ommen SR, Tajik J, Gersh BJ, Ackerman MJ. Genotyping in hypertrophic cardiomyopathy. Mayo Clin Proc. 2005; 85: 463-9.