RESUMO
OBJECTIVES: The aim of this study was to investigate the clinical expression of adenosine monophosphate-activated protein kinase (AMPK) gene mutations (PRKAG2) in adenosine monophosphate (AMP) kinase disease based on 12 years follow-up of known mutation carriers and to define the prevalence of PRKAG2 mutations in hypertrophic cardiomyopathy (HCM). BACKGROUND: Adenosine monophosphate-activated protein kinase gene mutations cause HCM with Wolff-Parkinson-White syndrome and conduction disease. METHODS: Clinical evaluation of 44 patients with known AMP kinase disease was analyzed. Mutation analysis of PRKAG2 was performed by fluorescent single-strand confirmation polymorphism analysis and direct sequencing of abnormal conformers in 200 patients with HCM. RESULTS: Only one additional mutation was identified. The mean age at clinical diagnosis in the 45 gene carriers was 24 years (median 20 years, range 9 to 55 years). Symptoms of palpitation, dypspnea, chest pain, or syncope were present in 31 (69%) gene carriers; 7 (15%) complained of myalgia and had clinical evidence of proximal myopathy. Skeletal muscle biopsy showed excess mitochondria and ragged red fibers with minimal glycogen accumulation. Disease penetrance defined by typical electrocardiogram abnormalities was 100% by age 18 years. Thirty-two of 41 adults (78%) had left ventricular hypertrophy (LVH) on echocardiography, and progressive LVH was documented during follow-up. Survival was 91% at a mean follow-up of 12.2 years. Progressive conduction disease required pacemaker implantation in 17 of 45 (38%) at a mean age of 38 years. CONCLUSIONS: The AMP kinase disease is uncommon in HCM and is characterized by progressive conduction disease and cardiac hypertrophy and includes extracardiac manifestations such as a skeletal myopathy, consistent with a systemic metabolic storage disease. Defects in adenosine triphosphate utilization or in specific cellular substrates, rather than mere passive deposition of amylopectin, may account for these clinical features.
Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/enzimologia , Complexos Multienzimáticos , Proteínas Serina-Treonina Quinases , Síndrome de Wolff-Parkinson-White/diagnóstico , Síndrome de Wolff-Parkinson-White/enzimologia , Proteínas Quinases Ativadas por AMP , Adolescente , Adulto , Cardiomiopatia Hipertrófica/terapia , Criança , Pré-Escolar , Desfibriladores Implantáveis , Diagnóstico Diferencial , Ecocardiografia , Eletrocardiografia Ambulatorial , Técnicas Eletrofisiológicas Cardíacas , Tolerância ao Exercício/fisiologia , Saúde da Família , Feminino , Seguimentos , Predisposição Genética para Doença/genética , Sistema de Condução Cardíaco/diagnóstico por imagem , Sistema de Condução Cardíaco/patologia , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Mutação/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Resultado do Tratamento , Síndrome de Wolff-Parkinson-White/terapiaRESUMO
BACKGROUND: We identified a gene (PRKAG2) that encodes the gamma-2 regulatory subunit of AMP-activated protein kinase (AMPK) with a mutation (Arg302Gln) responsible for familial Wolff-Parkinson-White (WPW) syndrome. The human phenotype consists of ventricular preexcitation, conduction abnormalities, and cardiac hypertrophy. METHODS AND RESULTS: To elucidate the molecular basis for the phenotype, transgenic mice were generated by cardiac-restricted expression of the wild-type (TG(WT)) and mutant(TG(R302Q)) PRKAG2 gene with the cardiac-specific promoter alpha-myosin heavy chain. ECG recordings and intracardiac electrophysiology studies demonstrated the TG(R302Q) mice to have ventricular preexcitation (PR interval 10+/-2 versus 33+/-5 ms in TG(WT), P<0.05) and a prolonged QRS (20+/-5 versus 10+/-1 ms in TG(WT), P<0.05). A distinct AV accessory pathway was confirmed by electrical and pharmacological stimulation and substantiated by induction of orthodromic AV reentrant tachycardia. Enzymatic activity of AMPK in the mutant heart was significantly reduced (0.009+/-0.003 versus 0.025+/-0.001 nmol x min(-1) x g(-1) in nontransgenic mice), presumably owing to the mutation disrupting the AMP binding site. Excessive cardiac glycogen was observed. Hypertrophy was confirmed by increases in heart weight (296 versus 140 mg in TG(WT)) and ventricular wall thickness. CONCLUSIONS: We have developed a genetic animal model of WPW that expresses a mutation responsible for a familial form of WPW syndrome with a phenotype identical to that of the human, including induction of supraventricular arrhythmia. The defect is due to loss of function of AMPK. Elucidation of the molecular basis should provide insight into development of the cardiac conduction system and accessory pathways.
Assuntos
Cardiomegalia/genética , Modelos Animais de Doenças , Sistema de Condução Cardíaco/fisiopatologia , Complexos Multienzimáticos/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Taquicardia por Reentrada no Nó Atrioventricular/genética , Síndrome de Wolff-Parkinson-White/genética , Proteínas Quinases Ativadas por AMP , Monofosfato de Adenosina/metabolismo , Substituição de Aminoácidos , Animais , Sítios de Ligação/genética , Estimulação Cardíaca Artificial , Cardiomegalia/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Camundongos , Complexos Multienzimáticos/deficiência , Complexos Multienzimáticos/genética , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Miocárdio/enzimologia , Cadeias Pesadas de Miosina/genética , Especificidade de Órgãos , Fenótipo , Mutação Puntual , Regiões Promotoras Genéticas/genética , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Taquicardia por Reentrada no Nó Atrioventricular/enzimologia , Taquicardia por Reentrada no Nó Atrioventricular/fisiopatologia , Síndrome de Wolff-Parkinson-White/enzimologia , Síndrome de Wolff-Parkinson-White/fisiopatologiaRESUMO
Mutations in the gene encoding the gamma(2) subunit of the AMP-activated protein kinase (AMPK) have recently been shown to cause cardiac hypertrophy and ventricular pre-excitation (Wolff-Parkinson-White syndrome). We have examined the effect of four of these mutations on AMPK activity. The mutant gamma(2) polypeptides are all able to form functional complexes following co-expression with either alpha(1)beta(1) or alpha(2)beta(1) in mammalian cells. None of the mutations caused any detectable change in the phosphorylation of threonine 172 within the alpha subunit of AMPK. Consequently, in the absence of an appropriate stimulus the mutant complexes, like the wild-type complex, exist in an inactive form demonstrating that the mutations do not lead to constitutive activation of the kinase. Three of the mutations we studied occur within the cystathionine beta-synthase (CBS) domains of gamma(2). Two of these mutations lead to a marked decrease in AMP dependence, whereas the third reduces AMP sensitivity. These findings suggest that the CBS domains play an important role in AMP-binding within the complex. In contrast, a fourth mutation, which lies between adjacent CBS domains, has no significant effect on AMPK activity in vitro. These results indicate that mutations in gamma(2) have different effects on AMPK function, suggesting that they may lead to abnormal development of the heart through distinct mechanisms.
Assuntos
Cardiomegalia/genética , Proteínas de Transporte , Complexos Multienzimáticos/química , Mutação , Proteínas Serina-Treonina Quinases/química , Proteínas de Saccharomyces cerevisiae , Síndrome de Wolff-Parkinson-White/genética , Proteínas Quinases Ativadas por AMP , Sequência de Aminoácidos , Substituição de Aminoácidos , Cardiomegalia/enzimologia , Humanos , Cinética , Dados de Sequência Molecular , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Mutagênese , Mutagênese Sítio-Dirigida , Fosforilação , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Subunidades Proteicas , Saccharomyces cerevisiae/enzimologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Estresse Mecânico , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Síndrome de Wolff-Parkinson-White/enzimologiaRESUMO
We evaluated postoperative myocardial enzymes and function associated with cryoablation in 20 patients with Wolff-Parkinson-White syndrome undergoing surgical treatment for a single left-sided accessory conduction pathway. Ten patients underwent endocardial atrial incision with cryoablation using CO2 at -60 degrees C for 120 sec (group A), while the remaining 10 patients did not receive cryoablation (group B). Levels of aspartate aminotransferase (GOT), lactate dehydrogenase (LDH), and creatine kinase (CK-MB) on postoperative days 1, 2, and 3 were higher in patients in group A than in group B (p < 0.05). However, mean values remained low (GOT, 120.5 IU/L; LDH, 1105.1 IU/L; CK-MB, 76.3 IU/L). No electrocardiographic changes were detected. Parameters of cardiac function, including cardiac index, stroke volume index, systemic vascular resistance, and ejection fraction, remained unchanged during the postoperative period in both groups. Furthermore, 201Tl cardiac scintigraphy demonstrated no evidence of myocardial perfusion defects due to cryoablation in group A. In conclusion, myocardial damage induced by cryoablation is very minor and is not associated with any clinical impairment of cardiac function.