Recent studies on dilated cardiomyopathy caused by TTN mutations in children / 中国当代儿科杂志

The mutations of TTN gene that encodes titin are the most common mutation type among the genetic causes of dilated cardiomyopathy (DCM). This article reviews the worldwide studies on potential molecular pathogenesis (transcription, post-translational modification, etc.), clinical phenotypes, and gene therapies of pediatric DCM caused by TTN mutations, with the hope of providing a reference for the precision treatment of pediatric DCM caused by TTN mutations.

Miocardiopatía dilatada en el niño / Dilated cardiomyopathy in children

Las miocardiopatías (MC) son enfermedades del músculo cardíaco infrecuentes, con una incidencia anual de 1.1-1.2 casos por 100.000 niños. La miocardiopatía dilatada (MCD) es la principal forma, se caracteriza por dilatación ventricular y disfunción sistólica, y es causa importante de insuficiencia cardíaca congestiva (ICC). Las etiologías en niños son múltiples, siendo idiopáticas en el 50%-70%. En la evaluación de un niño con MCD es fundamental descartar causas secundarias potencialmente reversibles. El ecocardiograma es la principal herramienta diagnóstica: permite establecer el fenoti po cardíaco, grado de compromiso funcional, y la evolución y respuesta al tratamiento médico. El pronóstico es limitado, siendo mejor en pacientes menores a 1 año al momento de presentación, post miocarditis, o con menor grado de disfunción sistólica ventricular. En los primeros 2 años post presentación alrededor de 20% tienen normalización de la función ventricular; 40%-50% fallece o requiere un trasplante cardíaco (TC) en los primeros 5 años. El tratamiento médico se basa en recomendaciones de adultos, siendo la evidencia pediátrica muy limitada. El TC es la terapia definitiva en pacientes con ICC terminal, con excelentes resultados a corto y mediano plazo. Una proporción importante de pacientes requiere estabilización en lista de espera, incluyendo asistencia mecánica circulatoria como puente a trasplante. El objetivo de este artículo es actualizar la información dis ponible en etiología, mecanismos fisiopatológicos, factores pronósticos, y tratamiento de la MCD en niños.

Pediatric cardiomyopathies are infrequent diseases of the cardiac muscle, with an annual inciden ce of 1.1 to 1.2 per 100,000 children. Dilated cardiomyopathy (DCM) is the predominant form, characterized by ventricular dilatation and systolic dysfunction. Etiologies are multiple, with at least 50%-70% of cases being idiopathic. When assessing a child with DCM, secondary potentially reversible causes must be ruled out. The main diagnostic tool is the echocardiogram which allows the identification of cardiac phenotype, to establish the degree of functional compromise, and res ponse to medical therapy. Prognosis is limited but more favorable in infants younger than 1 year at the onset, post myocarditis, or with a lesser degree of ventricular dysfunction. At least 20% of patients may recover ventricular function in the first 2 years after the onset and 40%-50% may die or need heart transplant in the first 5 years. Medical therapy is mainly based on adult experience with limited scientific evidence in children. Heart transplant is the therapy of choice in patients with end-stage disease, with excellent short- and medium-term survival. A significant proportion of patients may require stabilization on the waiting list, including the use of mechanical circulatory support as a bridge to transplantation. The purpose of this revision is to update the available infor mation on etiology, physiopathological mechanisms, prognostic factors, and management of DCM in children.

Miocardiopatía dilatada e insuficiencia cardíaca grave: Puesta al día para el médico pediatra / Dilated cardiomyopathy and severe heart failure: An update for pediatricians

La miocardiopatía dilatada es la principal causa de insuficiencia cardíaca que lleva a trasplante cardíaco. Su pronóstico es variable y depende de la etiología, la edad de presentación y el grado de insuficiencia cardíaca. El manejo está orientado a minimizar los síntomas y evitar la progresión de la enfermedad; se requiere de una evaluación integral en la pesquisa de comorbilidades y prevención de complicaciones que permitan mejorar la condición general de estos niños y atenuar su pronóstico. A continuación, se realiza una revisión orientada al manejo multidisciplinario que el pediatra debería considerar a la hora de enfrentarse a este tipo de pacientes.

Dilated cardiomyopathy is the main cause of heart failure leading to heart transplant. Its prognosis is variable and depends on the etiology, the patient's age at onset, and the severity. The management of dilated cardiomyopathy is aimed at minimizing symptoms and preventing disease progression; it requires a comprehensive screening for comorbidities and the prevention of complications to improve the overall status of these children and mitigate their prognosis. Here we present a review oriented at the multidisciplinary management that pediatricians should consider when seeing these patients.

Miocardiopatia não compactada: um relato de caso na região de Presidente Prudente / Noncompaction cardiomyopathy: a case report in the Presidente Prudente region

A miocardiopatia não compactada (MNC) é uma cardiopatia rara e congênita. Sua origem, possivelmente, ocorre durante o desenvolvimento embrionário, devido às alterações genéticas, cursando com insuficiência cardíaca, arritmia, precordialgia e tromboembolismo venoso. Nesse estudo, descreve-se o caso de uma mulher de 34 anos de idade, diagnosticada com MNC e em acompanhamento em hospital terciário, no oeste do interior paulista, junto ao departamento de Cardiologia. Inicialmente, a paciente apresentou sintomas arrítmicos associados à precordialgia, refratários ao tratamento antiarrítmico. O quadro progrediu, havendo dispneia e sudorese. Diante disso, iniciou-se investigação aprofundada, cogitando-se MNC. Objetivou-se demonstrar o quadro clínico inicial, a progressão da sintomatologia e a eficácia do seguimento realizado pelos profissionais que a assistem

Noncompaction cardiomyopathy (NCC) is a rare congenital heart disease possibly originating during embryonic development due to genetic changes, and resulting in heart failure, arrhythmia, precordialgia and venous thromboembolism. This study describes the case of a 34-year-old woman, diagnosed with NCC in follow-up with the Cardiology Department at a tertiary hospital in the west of the state of São Paulo. Initially, the patient presented arrhythmic symptoms associated with precordialgia, refractory to antiarrhythmic treatment; the symptoms progressed, with dyspnea and excessive sweating. Therefore, an in-depth investigation was initiated, considering NCC. The objective was to demonstrate the initial clinical symptoms, progression of the symptomatology, and the effectiveness of the follow-up performed by the attending professionals

Ablação com mapeamento eletroanatômico de taquicardia ventricular recorrente refratária a terapia medicamentosa na cardiomiopatia dilatada isquêmica em portador de cardiodesfibrilador multissítio / Ablation with electroanatomic mapping of refractory recurrent ventricular tachycardia to drug therapy in ischemic dilated cardiomyopathy in patients carrying a multisite cardiac defibrillator

As arritmias ventriculares em portadores de cardiomiopatia isquêmica estão diretamente relacionadas ao aumento da morbimortalidade, sendo sua recorrência associada a pior prognóstico. A despeito da otimização do tratamento medicamentoso, muitos são os pacientes refratários, e, nesse contexto, a ablação por adiofrequência torna-se uma importante alternativa terapêutica diante da refratariedade ao tratamento convencional. O mapeamento eletroanatômico permite visualização das áreas de fibrose e dos istmos de condução, aumentando as taxas de sucesso desse procedimento

Ventricular arrhythmias in ischemic cardiomyopathy patients are directly related to increased morbidity and mortality, and recurrence is associated to a worse prognosis. Despite the optimization of drug therapy, many patients are refractory to conventional therapy and in this context, radiofrequency ablation becomes an important therapeutic alternative. Electroanatomic mapping allows the visualization of fibrosis and isthmus conduction areas, increasing the success rates of this procedure

Cardiomiopatia hipertrófica dilatada com síndrome de Wolff- Parkinson-White / Dilated hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome

A cardiomiopatia hipertrófica é uma doença genética com apresentação, prognóstico e estratégias de tratamento variáveis. A visibilidade ligada à cardiomiopatia hipertrófica refere-se em grande parte a seu reconhecimento como causa comum de taquiarritmias e morte súbita cardíaca. O cardiodesfibrilador implantável é aceito como tratamento definitivo para prevenção de morte súbita, especialmente em pacientes de alto risco. Apesar da baixa prevalência, a via acessória é encontrada em 5% dos pacientes com cardiomiopatia hipertrófica e a ablação é o método de escolha, em decorrência do risco de taquiarritmias atriais. Relatamos o caso de um paciente com cardiomiopatia hipertrófica, em fase dilatada, com via acessória.

Hypertrophic cardiomyopathy is a genetic disease with variable presentation, prognosis and treatment strategies. The visibility linked to hypertrophic cardiomyopathy to a large extent refers to its recognition as a common cause of tachyarrhythmias and sudden cardiac death. Implantable cardiac defibrillator is accepted as definitive treatment for the prevention of sudden death, especially in high-risk patients. Despite the low prevalence, the accessory pathway is found in 5% of patients with hypertrophic cardiomyopathy and ablation is the method of choice due to risk of atrial tachyarrhythmias. We report the case of a patient with dilated hypertrophic cardiomyopathy and an accessory pathway.

Evolución clínica y ecográfica posterior a terapia de resincronización cardíaca / Clinical and echocardiographi follow up after cardiac resynchronization

Antecedentes: La terapia de resincronización cardíaca (TRC) está adquiriendo importancia como tratamiento complementario en insuficiencia cardíaca avanzada. En Chile, el seguimiento clínico y ecográfico de este grupo de pacientes no ha sido suficientemente investigado y se desconoce la realidad nacional. Objetivos: Describir los cambios clínicos y eco-gráficos posterior a TRC en los pacientes del servicio de cardiología del Hospital Carlos Van Buren de Valparaíso, sometidos al procedimiento entre los años 2013 y 2015. Métodos: Se realizó un análisis descriptivo de 10 pacientes con diagnóstico de miocardiopatía dilatada sometidos a TRC, recolectándose variables clínicas y ecográficas previo y al sexto mes post-procedimiento. Se utilizó frecuencias y medianas para describir los resultados. Se definió como respondedores aquellos pacientes que mejoraron su capacidad funcional luego de la intervención. Resultados: Del total de pacientes sometidos a TRC, hubo un 30% de no respondedores, en los cuales no se encontraron predictores de fracaso. En los respondedores se observó mejoría de la capacidad funcional y al menos una de las siguientes: aumento de la fracción de eyección, disminución del diámetro telediastólico del ventrículo izquierdo y reducción del grado de regurgitación mitral. No se observó reducción en el número de hospitalizaciones al año. Conclusiones: Se demuestra la utilidad de la TRC en el tratamiento de la insuficiencia cardíaca avanzada en un grupo seleccionado de pacientes. Se necesitan estudios locales con mayor número de paciente para representar nuestra realidad nacional.

Background: Cardiac resynchronization therapy (CRT) is gaining relevance as an important therapy in patients with advanced heart failure. In Chile, the clinical and echocardiographic follow-up of these patients has not been sufficiently documented. Aim: To describe the clinical and echocardiographic changes after CRT in patients treated at the cardiology department of the Carlos Van Buren Hospital in Valparaiso, undergoing the procedure between 2013 and 2015. Methods: A descriptive analysis of 10 patients with a diagnosis of dilated cardiomyopathy submitted to CRT was performed. Clinical and echocardiographic data was collected before and sixth months after the procedure. Frequency and median were used to describe the results. Responders were defined as patients who improved their functional capacity after the intervention. Results: Of all patients undergoing CRT, there were 3 (30%) non-responder patients. In responders improvement in functional capacity and increased ejection fraction or decreased left ventricular diastolic diameter or reduction of mitral regurgitation was observed. No reduction was observed in the number of hospitalizations annually. Conclusion: The results support the usefulness of CRT in treating advanced heart failure in a selected group of patients. Further studies are needed to better define our national reality and predictors of a favorable response after the procedure.

Uso de tomografia por emissão do pósitrons acoplada a tomografia computadorizada para orientar a estratégia cirúrgica do tratamento de complicação infecciosa em portador de marcapasso / Use of positron-emissiontomography combined with a multidetection helical computed tomography to guide the surgical strategy in the treatment of pacemaker infection

Dentre as complicações relacionadas aos dispositivos cardíacos eletrônicos implantáveis, os processosinfecciosossão os de maior gravidade e de mais difícil tratamento. A taxa média de infecções relacionadas a esses dispositivoscardíacos relatada na literatura pode variar de 1% a 7% e resultam em importante impacto na morbimortalidade.Neste artigo relatamos o caso clínico de um paciente com infecção crônica relacionada a cabo-eletrodo epicárdicoabandonado, com manifestações recorrentes, em que os achados da tomografia por emissão de pósitrons acoplada atomografia computadorizada utilizando 18F-fluoro-2-deoxiglicose ajudaram o correto entendimentodo processo e acondução do tratamento cirúrgico.

Among the complications related to cardiac implantable electronic devices, infections are the mostserious and more difficult to treat. The mean rate of infections related to these cardiac devices reported in theliterature ranges from 1% to 7% and result in significant impact on morbidity and mortality. We report theclinical case of a patient with chronic infection related to abandoned epicardial pacemaker lead, with recurrentmanifestations, in which the findings of 18F-fluoro-2-deoxyglucose positron-emission tomography combinedwith a multidetection helical computed tomography were useful for a proper understanding of the process and toguide the surgical treatment.

Superior vena cava thrombosis with peripartum dilated cardiomyopathy

A 30 years multiparous female with history of emergency caesarean section 10 days back was referred to us with cough, severe breathlessness at rest, orthopnea with pain in neck and arms. Clinical examination revealed signs of heart failure. Echocardiography showed ejection fraction of 15%, with no right ventricular strain. A diagnosis of peripartum cardiomyopathy was made. Doppler ultrasound of neck veins showed bilateral internal jugular vein thrombosis. Subsequent multislice CT examination showed thrombosis of superior vena cava and both internal jugular veins [with collateral formation] and pulmonary embolism. There were no mediastinal abnormalities on the CT scan. Her thrombophilia screen and CT scan brain was normal. She was managed in collaboration with cardiologist. Following treatment with subcutaneous enoxaparin therapy and warfarin her symptoms of upper limb pain improved. She responded very well to medical therapy for heart failure with marked improvement of NYHA functional class

Miocardiopatía dilatada aguda asociada con eosinofilia / Eosinophilia-linked acute dilated myocardiopathy

La miocardiopatía dilatada aguda con insuficiencia cardíaca parece constituir una forma de presentación del compromiso miocárdico por eosinofilia periférica incluso en pacientes de avanzada edad

Hypothyroidism: A reversible aetiology of dilated cardiomyopathy.

Hypothyroidism has various cardiovascular manifestations, impairment of LV diastolic function being the commonest. We hereby report a young female who presented to us with features of congestive heart failure and on subsequent work-up she was diagnosed as a case of dilated cardiomyopathy of reversible aetiology, i.e., hypothyroidism.

Comparação de parâmetros eletrofisiológicos das estimulações cardíacas endocárdicas septal e apical / Comparison of electrophysiological parameters of septal and apical endocardial cardiac stimulation

FUNDAMENTO: A estimulação endocárdica convencional do ventrículo direito (VD) ocasiona alargamento do QRS e dessincronização do miocárdio, comprometendo a função ventricular. Com a necessidade de estimulação menos deletéria, a estimulação septal do VD tem sido mais utilizada. Eventualmente têm sido relatados limiares mais altos e ondas R menores na estimulação septal. OBJETIVO: Comparar os parâmetros das estimulações apical e septal, intrapaciente, para verificar se existem diferenças que possam interferir na escolha do ponto de estimulação. MÉTODOS: Estudo prospectivo controlado. Foram incluídos 25 pacientes, com 67,2 ± 9 anos, 10 (40%) mulheres, com indicações de marca-passo por bradiarritmias. Etiologias foram degenerativa em nove (36%), coronariopatia em oito (32%), doença de Chagas em sete (28%), e valvopatia em um (4%) pacientes. Foram utilizados eletrodos de fixação ativa e avaliados os limiares de comando, impedância e onda R uni e bipolares no implante e após seis meses. RESULTADOS: A média aguda dos limiares de comando, ondas R e impedâncias unipolares/bipolares septais x apicais foram, respectivamente, 0,73x0,74V e 0,73x0,78V; 10x9,9 mV e 12,3x12,4 mV; 579x621 Ω e 611x629 Ω. Comparações entre parâmetros septais e apicais com teste t-pareado bicaudal demonstraram um P > 0,1. Após seis meses, a média dos limiares de comando, ondas R e Impedâncias unipolares/ bipolares septais x apicais foram, respectivamente, 0,5 x 0,72 V e 0,71 x 0,87 V; 11,4x9,5 mV e 12x11,2 mV; 423x426Ω e 578x550Ω, com P > 0,05, exceto comparando-se limiar de estimulação unipolar septal com apical unipolar p de 0,02. CONCLUSÃO: Utilizando comparações intrapaciente, não existem diferenças expressivas entre parâmetros eletrofisiológicos de estimulação septal e apical sendo que não há restrições para a escolha da estimulação septal em ventrículo direito.

BACKGROUND: The conventional right ventricle (RV) endocardial pacing leads QRS widening and desynchronization myocardial compromising ventricular function. With the need for stimulation less deleterious, RV septal pacing has been used more. Eventually have been reported higher thresholds and smaller R waves in the septal stimulation. OBJECTIVE: To compare the parameters of the septal and apical stimulation, intra-patient, if there are any differences that may affect the choice of the point of stimulation. METHODS: A prospective controlled study. We included 25 patients, 67.2±9 years, 10 (40%) women with indications for pacemaker for bradyarrhythmias. Etiologies were degenerative in nine (36%), Coronary disease in eight (32%), Chagas disease in seven (28%), and valve disease in one (4%) patient. Electrodes were active fixation and assessed the thresholds of command, impedance and R wave in uniand bipolar implant and after six months. RESULTS: The average acute threshold command, R wave and impedance unipolar / bipolar septais x apicais were respectively 0.73 x 0.73V and 0,74V x 0,78V; 10 x 9,9mV and 12,3 x 12,4mV; 579 x 621Ω and 611 x 629Ω. Comparisons between parameters with septal and apical two-tailed paired t-test showed a P > 0.1. After six months, the mean control thresholds, R wave impedances and unipolar/bipolar septais x apicais were respectively 0.5V x 0 72V and 0.71V x 0,87V; 11.4 x 9,5mV and 12x11,2mV; 423x426 Ω and 578x550 Ω, with P > 0.05, except compared to unipolar pacing threshold septal apical unipolar P 0.02. CONCLUSION: Using intra-patient comparisons, no significant differences between electrophysiological parameters septal and apical pacing and there are no restrictions for choosing the right ventricular septal pacing.

Implante de eletrodo em veia ázigos: uma opção terapêutica para limiar de desfibrilação elevado / Azygos vein lead implantation: a therapeutic option for elevated defibrillation threshold

A avaliação do limiar de desfibrilação (DFT) durante o implante do cardioversor-desfibrilador (CDI) é uma etapa relevante do procedimento, uma vez que, em até 16% dos pacientes, podemos encontrar elevados DFT. Relatamos o caso de um paciente portador de cardiomiopatia dilatada (CMPD) idiopática submetido a implante de CDI biventricular. Durante o procedimento, apresentou elevado DFT e se mostrou resistente às modalidades terapêuticas usuais. Optamos pelo implante de eletrodo de desfibrilação em veia ázigos, com resolução do quadro.

The evaluation of the defibrillation threshold (DFT) during the implantation of a cardioverter-defibrillator (ICD) is an important stage of the procedure, as a high DFT can be found in up to 16% of patients. We report a patient with idiopathic dilated cardiomyopathy (DCM) submitted to a biventricular ICD implantation. During the procedure, the patient showed a high DFT and showed to be resistant to usual therapeutic modalities. We opted for the azygos vein defibrillation lead implantation, with good resolution.

Terapia de resincronización cardiaca en paciente con vena cava superior izquierda persistente: Caso clínico / Placement of a biventricular resynchronization device in a patient with a persistent left superior vena cava: Report of one case

Persistent left superior vena cava is the most common venous congenital malformation and is usually asymptomatic. Its presence could increase the difficulty for transvenous lead implantation. We report a 71-year-old woman with an idiopathic dilated cardiomyopathy, atrial fibrillation and heart failure that required biventri-cular resynchronization therapy. During the placement of the device a persistent left superior vena cava was detected. The device was placed without problems and the patient had a satisfactory postoperative evolution.

An unknown complication of peripherally inserted central venous catheter in a patient with ventricular assist device.

We report an unknown complication of peripherally inserted central venous catheter in a patient with Ventricular Assist Device. This rare complication led to the failure of the right ventricular assist device, which could be detrimental in patients with dilated cardiomyopathy.

Cell therapy in dilated cardiomyopathy: from animal models to clinical trials

Dilated cardiomyopathy can be the end-stage form and common denominator of several cardiac disorders of known cause, such as hypertensive, ischemic, diabetic and Chagasic diseases. However, some individuals have clinical findings, such as an increase in ventricular chamber size and impaired contractility (classical manifestations of dilated cardiomyopathy) even in the absence of a diagnosed primary disease. In these patients, dilated cardiomyopathy is classified as idiopathic since its etiology is obscure. Nevertheless, regardless of all of the advances in medical, pharmacological and surgical procedures, the fate of patients with dilated cardiomyopathy (of idiopathic or of any other known cause) is linked to arrhythmic episodes, severe congestive heart failure and an increased risk of sudden cardiac death. In this review, we will summarize present data on the use of cell therapies in animal models of dilated cardiomyopathies and will discuss the few clinical trials that have been published so far involving patients affected by this disease. The animal models discussed here include those in which the cardiomyopathy is produced by genetic manipulation and those in which disease is induced by chemical or infectious agents. The specific model used clearly creates restrictions to translation of the proposed cell therapy to clinical practice, insofar as most of the clinical trials performed to date with cell therapy have used autologous cells. Thus, translation of genetic models of dilated cardiomyopathy may have to wait until the use of allogeneic cells becomes more widespread in clinical trials of cell therapies for cardiac diseases.

Cardiomiopatia periparto / Peripartum cardiomyopathy

A cardiomiopatia periparto (CMPP) é uma forma de cardiomiopatia dilatada, caracterizada pelo desenvolvimento de insuficiência cardíaca sistólica no período entre o último mês da gravidez e os cinco meses pós-parto. A incidência estimada varia entre 1/1.300 a 1/15.000 gestações. Admitem-se como fatores de risco para CMPP a idade materna avançada, multiparidade, raça negra, gestação gemelar, obesidade, pré-eclâmpsia e doença hipertensiva gestacional. A etiologia da CMPP permanece incerta, mas possíveis causas têm sido propostas, incluindo miocardite, resposta imune anormal a gravidez, má resposta adaptativa hemodinâmica à gestação, citocinas ativadas pelo stress, infecção viral, uso prolongado de tocolíticos, hereditariedade, déficits nutricionais e distúrbios hormonais. Os sinais e sintomas presentes na CMPP são semelhantes aos que aparecem em pacientes com insuficiência cardíaca de outras causas. O diagnóstico é confirmado pelo ecocardiograma, que mostra objetivamente a presença de disfunção ventricular esquerda. O tratamento é semelhante ao da insuficiência cardíaca de outras etiologias, sendo os inibidores da enzima de conversão da angiotensina e os bloqueadores dos receptores da angiotensina II evitados durante a gravidez (devido aos efeitos tóxicos para o feto), porém indicados no período puerperal, não interferindo na lactação. O papel dos imunossupressores no tratamento da CMPP ainda é controverso. Estudos bem desenhados são fundamentais para que se descubra a etiologia, que poderá orientar um tratamento específico, levando a uma melhor evolução dos pacientes com essa doença.

Peripartum cardiomyopathy (PPCM) is a disorder of dilated cardiomyopathy and left ventricular dysfunction occurring in the last month of pregnancy of within five months postpartum. Incidence of PPCM ranges from 1/1.300 to 1/15.000 pregnancies. Risk factors for PPCM include advanced maternal age, multiparity, African race, twin pregnancies, obesity, preeclampsia and gestacional hypertension. The etiology of PPCM is unknown, but many hypotheses have been proposed including myocarditis, abnormal immune response to pregnancy, maladaptative response to the hemodynamic stresses of pregnancy, stress activated cytokines, viral infection, prolonged tocolysis, heredity, nutritional and hormonal disorders. Symptons and signs of PPCM are similar to the one of those patients with heart failure of other causes. The diagnosis is confirmed with the echocardiographic identification of left ventricular systolic dysfunction. The treatment of PPCM is similar to medical therapy for other forms of cardiac failure. In spite of that, the use of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker is contraindicated because of the potencial toxic effects on the fetus; they can be used in puerperal period and during lactation. Further researches are needed to discover the peripartum cardiomyopathy's etiology; they will be able to guide a specific treatment and a better prognostic for the patients with this disease.