Identificación y tratamiento de los pacientes con miocardiopatía hipertrófica y riesgo de muerte súbita

doi:10.1016/S0300-8932(00)75069-X

Revista Española de Cardiología

Volume 53, Issue 1, 2000, Pages 123-130

https://doi.org/10.1016/S0300-8932(00)75069-X Get rights and content

El principal objetivo en la investigación de la miocardiopatía hipertrófica en los últimos 20 años ha sido la identificación y tratamiento de los pacientes con riesgo de muerte súbita. La muerte súbita es un problema importante en esta enfermedad por su incidencia (el 1% anual en poblaciones no seleccionadas y el 4-6% en algunas series) y porque afecta principalmente a pacientes jóvenes, en muchas ocasiones previamente asintomáticos.

Hoy día sabemos que la miocardiopatía hipertrófica no es una sola enfermedad, sino un grupo de enfermedades producidas por mutaciones en proteínas del sarcómero, cuya expresión fenotípica depende de múltiples factores modificadores genéticos y ambientales. Aunque los estudios genéticos no constituyen actualmente una alternativa práctica en la estratificación de riesgo de los pacientes con miocardiopatía hipertrófica, es importante tener en cuenta estos nuevos conocimientos en la valoración pronóstica de los pacientes.

En este artículo revisamos los datos publicados acerca de la estratificación de riesgo en la miocardiopatía hipertrófica y exponemos nuestra opinión sobre las opciones terapéuticas disponibles y sus indicaciones en la prevención de la muerte súbita.

During the last 20 years, the principal objective in hypertrophic cardiomyopathy research has been the refinement of algorithms for the identification and treatment of patients at risk of sudden death. Sudden death is an important problem in hypertrophic cardiomyopathy, with an incidence of 4-6% in referral populations and approximately 1% in non-referral centers and because it affects young and often asymptomatic patients.

We now know that hypertrophic cardiomyopathy is not a single disease, but a group of diseases caused by mutations in genes encoding different sarcomeric proteins. The phenotypic expression depends on multiple modifying genetic and environmental factors. Even though genetic testing is not presently a practical approach in hypertrophic cardiomyopathy risk stratification, it is important to consider new genetic data in the prognostic evaluation of patients.

In this paper, we review the published data on risk stratification in hypertrophic cardiomyopathy and we set forth our opinion with regard to the available therapeutic options and their indications in the prevention of sudden death.

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Cited by (25)

A homozygous MYBPC3 gene mutation associated with a severe phenotype and a high risk of sudden death in a family with hypertrophic cardiomyopathy
2009, Revista Espanola de Cardiologia
El estudio genético puede resultar una pieza clave en la evaluación integral de la miocardiopatía hipertrófica familiar y en el desarrollo de una medicina individualizada. Hay pocos casos descritos, pero existe un grupo de pacientes con genotipos complejos asociados a manifestación severa de la enfermedad y alto riesgo de muerte súbita. Presentamos una familia caracterizada por evolución precoz a disfunción sistólica y diastólica en algunos de sus integrantes y muerte súbita a edades tempranas en otros. Se detectó una mutación en homocigosis (IVS6+5G>A) en el gen de la proteína C de unión a la miosina, no descrita previamente, que nos permitió explicar el fenotipo de los afectados, estimar el riesgo en otros familiares y ofrecer consejo genético.
Genetic studies can play a key role in the comprehensive evaluation of familiar hypertrophic cardiomyopathy and in the development of individualized medicine. Although only a few cases have been described, there exists a group of patients with complex genotypes that are associated with severe disease manifestations and a high risk of sudden death. We describe a family in which some members experienced the early development of systolic and diastolic dysfunction while others experienced sudden death at a young age. We identified a novel homozygous mutation (IVS6+5G>A) in the myosin-binding protein-C gene that explained the phenotype of affected individuals and that enabled us to estimate the risk in other family members and to offer genetic counseling.
Beta-myosin heavy-chain gene mutations in patients with hypertrophic cardiomyopathy
2006, Revista Espanola de Cardiologia
Determinar la frecuencia de mutaciones en el gen de la cadena pesada de la betamiosina (MYH7) en una cohorte de pacientes con miocardiopatía hipertrófica (MCH) y en sus familiares, y analizar la correlación entre genotipo y fenotipo.
Detección de polimorfismo en la conformación de hebras monocatenarias y secuenciación de fragmentos con movilidad anormal del gen MYH7 en 128 casos índice consecutivos con MCH. Comparación de fenotipo entre pacientes con y sin mutaciones y descripción del fenotipo de las familias identificadas.
Identificamos 11 mutaciones en 13 familias (10%), 7/11 previamente descritas. La mutación I736T se identificó en 3 familias y la A797T en 2. Un caso presentó 2 mutaciones (I736T y R787H). Las mutaciones fueron más frecuentes en pacientes con antecedentes familiares de muerte súbita (31%) y con hipertrofia severa (39% con grosor ≥ 30 mm). Había mutación en 29 de 42 miembros de las 13 familias, incluidos 6 (20%) portadores sanos (edad ≤ 36 años). Había antecedentes de muerte súbita en 9 familiares de 4 familias (4 en 2 familias con I736T, uno con A797T, uno con R870H y 2 con A901P).
Las mutaciones en MYH7 aparecen en un 10% de nuestras familias y son más frecuentes cuando hay antecedentes familiares de muerte súbita o hipertrofia severa. La mayor parte había sido descrita previamente y algunas se repiten en varias familias. Ciertas mutaciones muestran una correlación genotipo-fenotipo estable, mientras que en otras, las marcadas diferencias entre casos índice y familiares hacen sospechar la presencia de factores genéticos adicionales que debemos identificar.
To determine the frequency of mutations in the beta-myosin heavy-chain gene (MYH7) in a cohort of patients with hypertrophic cardiomyopathy (HCM) and their families, and to investigate correlations between genotype and phenotype
Single-strand conformation polymorphism analysis and sequencing of fragments with abnormal MYH7 gene mobility were carried out in 128 consecutive index patients with HCM. The phenotypes of patients with and without mutations were compared and the phenotypes of identified families were recorded.
A total of 11 mutations were found in 13 families (10%); 7/11 had been previously described. The I736T mutation was found in three families and the A797T in two. One patient had two mutations (i.e., I736T and R787H). Mutations were more frequent in patients with a family history of sudden death (31%) and in those with severe hypertrophy (39% had a thickness ≥30 mm). Mutations were found in 29 of 42 members of the 13 families, including six family members (20%) who were healthy carriers and aged ≤36 years. Sudden death had occurred in eight members of four families: four in two families with the I736T mutation, one in a family with A797T, one in a family with R870H, and two in a family with A901P.
MYH7 mutations were present in 10% of our families. Mutations were more frequent in patients with a family history of sudden death and in those with severe hypertrophy. Most mutations had been described previously. Some appeared in several families. For some mutations, the correlation between genotype and phenotype was stable, while for others, there were marked differences between the phenotypes of the index patients and their relatives, suggesting the presence of additional genetic factors that have yet to be identified.
The implantable cardioverter-defibrillator and hypertrophic cardiomyopathy. Experience at three centers
2006, Revista Espanola de Cardiologia
El desfibrilador automático implantable (DAI) es el tratamiento recomendado en la miocardiopatía hipertrófica (MCH) de alto riesgo, aunque no hay acuerdo en sus indicaciones. Hay pocos datos sobre su utilización en nuestro país. El objetivo es describir las características de los pacientes con MCH a los que se les implantó un DAI y analizar los resultados de esta terapia.
Se analizaron los factores de riesgo de muerte súbita en los pacientes portadores de DAI de 3 centros con consultas dedicadas a la MCH (antecedentes personales y familiares de muerte súbita, síncope recurrente, grosor ≥ 30 mm y gradiente subaórtico > 30 mmHg, respuesta anormal de la presión al esfuerzo y taquicardia ventricular no sostenida) y la indicación del implante. Se realizó un seguimiento periódico y se registraron las terapias adecuadas e inadecuadas.
De 726 pacientes, 45 (6,2%) eran portadores de DAI (edad de 43 ± 20 años). La proporción de pacientes con DAI en los 3 centros fue muy variable, a pesar de que las características de los pacientes eran similares. La indicación fue prevención primaria en 27 pacientes y secundaria en 18. Con un seguimiento de 32 meses, 10 pacientes (22%) recibieron tratamiento adecuado (9 de prevención secundaria y uno de prevención primaria). La tasa anual de tratamientos adecuados fue del 11,1% en prevención secundaria y del 1,6% en prevención primaria. El único factor asociado con el tratamiento adecuado fue el antecedente de taquicardia ventricular sostenida o fibrilación ventricular (riesgo relativo [RR] = 13,3; p = 0,014).
En consultas dedicadas a la MCH, el porcentaje de pacientes portadores de DAI varía en función del grado de selección de la población de origen. La incidencia de terapias adecuadas es elevada en prevención secundaria (el 50% en 3 años).
Although implantable cardioverter-defibrillators (ICDs) are recommended for high-risk patients with hypertrophic cardiomyopathy (HCM), there is no agreement on their general use. Moreover, little information is available on ICD use in this setting in Spain. Our aims were to describe the characteristics of HCM patients who received ICDs at three hospitals in Spain, and to study indications for device implantation and the results of follow-up in device users.
We evaluated risk factors for sudden death in HCM patients with ICDs, including family history of sudden death, recurrent syncope, maximum wall thickness ≥30 mm, left ventricular outflow pressure gradient >30 mmHg, abnormal blood pressure response to exercise, and nonsustained ventricular tachycardia. During regular follow-up, appropriate and inappropriate administration of ICD therapy was recorded.
Of 726 HCM patients, 45 (6.2%) had an ICD (mean age 43 [20] years). The proportion of patients with ICDs at the three centers studied was highly variable despite patients’ clinical characteristics being similar. The indication for implantation was primary prevention in 27 patients and secondary prevention in 18. During follow-up (median 32 months), ICD therapy was administered appropriately in 10 (22.0%) patients (in nine, as secondary prevention and, in one, as primary prevention). The annual appropriate ICD therapy rate was 11.1% for secondary prevention and 1.6% for primary prevention. Two patients received an ICD to treat ventricular fibrillation and eight, to treat sustained ventricular tachycardia. The only significant predictor of appropriate ICD therapy was a history of sustained ventricular tachycardia or ventricular fibrillation (hazard ratio =13.3, P=.014).
The percentage of HCM patients undergoing ICD implantation at Spanish hospitals was highly variable, possibly due to different selection criteria. When used as secondary prevention, ICD therapy was administered appropriately in a high proportion of cases (50% in 3 years).
Hypertrophic myocardiopathy: How to predict its evolution?
2004, Medicina Clinica
Hypertrophic myocardiopathy. Management during pregnancy and labour
2004, Clinica e Investigacion en Ginecologia y Obstetricia
La miocardiopatia hipertrófica no es una enfermedad aislada, sino un grupo caracterizado por la mutación de diferentes genes codificadores de proteínas sarcoméricas. Su expresión fenotípica depende de diferentes factores genéticos y ambientales. En este artículo se describe un caso de miocardiopatia hipertrófica en un contexto familiar durante el embarazo, y se describe su tratamiento durante éste y en el parto.
Hypertrophic cardiomyopathy is not a single disease, but a group of diseases caused by mutations in genes encoding different sarcomeric proteins. The phenotype expression depends on multiple genetic and environmental factors. In this paper, we describe a familial case of hypertrophic cardiomyopathy during pregnancy, and the options available for management during pregnancy and delivery.
Direct detection of malignant mutations in patients with hypertrophic cardiomyopathy
2003, Revista Espanola de Cardiologia
Hemos determinado la prevalencia de mutaciones consideradas malignas en los genes de la cadena pesada de la betamiosina (MYH7, 11 mutaciones) y la troponina T (TNNT2, 5 mutaciones) en 30 pacientes con miocardiopatía hipertrófica (MCH) menores de 60 años, de los que el 83% tenía antecedentes familiares de MCH y/o muerte súbita. Empleamos la reacción en cadena de la polimerasa (PCR) seguida de digestión con una enzima de restricción y electroforesis en geles de agarosa.
El análisis directo nos permitió identificar alguna de las 16 mutaciones en 2 de los 30 pacientes (7%): una mujer diagnosticada a los 25 años era portadora de la mutación MYH7-453 cisteína, y otra mujer, de 60 años, era portadora de la mutación TNNT2-278 cisteína. Estos casos ilustran la gran heterogeneidad clínica que caracteriza a los portadores, que van desde la hipertrofia grave o la muerte súbita temprana hasta la ausencia de síntomas en edades avanzadas de la vida.
We determined the prevalence of mutations considered malignant in the genes for beta-myosin heavy chain (MYH7, 11 mutations) and troponin T (TNNT2, 5 mutations) in 30 patients with hypertrophic cardiomyopathy aged 18 to 60 years, 83% of whom had familial antecedents of hypertrophic myocardiopathy or sudden death. Mutations were identified with polymerase chain reaction followed by restriction enzyme digestion and agarose gel electrophoresis.
Direct analysis identified 16 mutations in 2 of the 30 patients (7%): one women diagnosed at the age of 25 years as carrying the MYH7453cysteine mutation, and a 60-year-old women with the TNNT2278 cysteine mutation. These cases illustrate the considerable clinical heterogeneity that characterizes carriers of these mutations. Clinical manifestations can range from severe hypertrophy or early sudden death to the absence of symptoms up to advanced age.

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Identificación y tratamiento de los pacientes con miocardiopatía hipertrófica y riesgo de muerte súbitaIdentification and Treatment of Patients with Hypertrophhic Cardiomyopathy at Risk of Sudden Death

Prog Cardiovasc Dis

Am J Cardiol

Am J Cardiol

Am J Cardiol

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

Am Heart J

J Am Coll Cardiol

J Mol Cell Cardiol

Am Heart J

The management of hypertrophic cardiomyopathy

N Engl J Med

Recent advances in the molecular genetics of hypertrophic cardiomyopathy

Circulation

Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy

Nat Genet

Hypertrophic cardiomyopathy: interrelations of clinical manifestations, patophysiology, and therapy

N Engl J Med

Prevalence of hypertrophic cardiomyopathy in a population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA study. Coronary Artery Risk Development in (Young) Adults

Circulation

Clinical course and prognosis of hypertrophic cardiomyopathy in an outpatients population

N Engl J Med

Hypertrophic cardiomyopathy in Tuscany: clinical course and outcome in an unselected regional population

J Am Coll Cardiol

Hypertrophic cardiomyopathy: an important cause of sudden death

Arch Dis Child

Hypertrophic cardiomyopathy without hypertrophy: two families with myocardial disarray in the absence of increased myocardial mass

Br Heart J

Diagnostic value of electrocardiograhy and echocardiography for familial hypertrophic cardiomyopathy in a genotyped adult population

Circulation

Experience from clinical genetics in hypertrophic cardiomyopathy: proposal for new diagnostic criteria in adult members of affected families

Heart

Hypertrophic cardiomyopathy

Sudden death in hypertrophic cardiomyopathy: a profile of 78 patients

Circulation

Sudden death in hypertrophic cardiomyopathy: Assessment of patients at high risk

Circulation