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A Miocardiopatia hipertrófica foi descrita há mais de 50 anos e é a cardiopatia de causa genética mais comum no mundo. Pacientes portadores de miocardiopatia hipertrófica podem apresentar maior risco de eventos arrítmicos graves e morte súbita. Assim torna-se importante o desenvolvimento de técnicas de rastreio desse subgrupo de pacientes para, quando necessário, indicar tratamento específico como o implante de CDI. O realce tardio é a manifestação de fibrose nos exames de imagem como tomografia computadorizada do coração e/ou ressonância cardíaca em pacientes com cardiopatias e quando presente em grandes quantidades, pode estar relacionado a maior incidência de eventos fatais. O eletrocardiograma é ferramenta de baixo custo, não invasiva e difundida nos serviços de saúde brasileiros. O objetivo desse estudo é avaliar a correlação entre a presença e localização de realce tardio na tomografia computadorizada do coração e o achado de fibrose pelo escore de Selvester no eletrocardiograma de repouso de portadores de MCPH, determinar a prevalência de fibrose miocárdica entre os pacientes, comparando a sensibilidade, especificidade, valor preditivo positivo e negativo do escore de Selvester. Foram analisados 112 pacientes do ambulatório de miocardiopatia do Instituto Dante Pazzanese de Cardiologia portadores de miocardiopatia hipertrófica sendo incluídos 75 desses. Foram divididos em dois grupos: Portadores de CDI com 60 pacientes e sem CDI com 15 pacientes. Foram coletados dados clínicos, ecocardiográficos, eletrocardiografia digital e tomografia computadorizada do coração. Foram realizados os cálculos do escore de Selvester e a mensuração e localização de realce tardio nos cortes tomográficos dos pacientes. A correlação dos resultados foi analisada pelo método de regressão linear. As características e frequências mais marcantes do grupo foram sexo masculino 49,4%, idade 41,63 ± 15,16, classe funcional I/II - NYHA 90,6%, fibrilação atrial 21,3%, baixa prevalência de comorbidades como hipertensão arterial 37,3%, diabetes 4%, dislipidemia 17,3%, clearence de creatinina > 60mL/min em 100% e ausência de doença coronariana estabelecida, fração de ejeção do ventrículo esquerdo preservada de 69,9 ± 5,46, medida do septo interventricular de 21,04 ± 6,23 e prevalência de gradiente > 30mmHg na via de saída do ventrículo esquerdo de 37,3%. Dos fatores de risco clássicos, morte súbita familiar e história de síncope eram as mais prevalentes com 57,3% cada, o uso do beta-bloqueador ocorreu em 89,3%. A massa de fibrose pela tomografia computadorizada foi de 9,87 ± 10,79 equivalendo a porcentagem de 5,66 ± 6,16, tendo prevalência em 88% da amostra. Já pelo escore de Selvester, encontramos 8,44 ± 7,39 de porcentagem de fibrose com prevalência de 76%. Na análise de kappa para a variável categórica fibrose entre o escore de Selvester e a tomografia computadorizada do coração, foi encontrada fraca correlação com r = 0,38 (p < 0,01). Enquanto variável contínua aplicando o método de regressão linear, foi encontrada correlação forte com r = 0,7 (p < 0,01). A sensibilidade, especificidade, valor preditivo positivo e valor preditivo negativo do escore de Selvester para o diagnóstico de fibrose foram de, respectivamente, 84,8%, 88,8%, 98,2% e 44,4%. A localização da fibrose apresentou correlação fraca entre os métodos com r = 0,16 (p < 0,01). Os dados desse estudo indicam que há moderada correlação entre o escore de Selvester e o realce tardio pela tomografia computadorizada na quantificação de fibrose em pacientes portadores de miocardiopatia hipertrófica. / Hypertrophic cardiomyopathy is considered the most common genetic cardiovascular disease and has been recognized for 50 years. Patients with hypertrophic cardiomyopathy may present risk of arrhythmic events and sudden cardiac death. Thus, it is important to develop screening techniques for this subgroup of patients to indicate, when necessary, specific treatment as implantable cardioverter defibrillator. Late enhancement is fibrosis manifestation in images exam as multidetector computed tomography and/or magnetic cardiac resonance and if present in large quantities may be related to a higher incidence of fatal events. The electrocardiogram is a low-cost, non-invasive tool that is present in most Brazilian health services. The purpose of this study was to test the presence and location correlation between the Selvester and the late enhancement in the multidetector computed tomography, to determine the prevalence of myocardial fibrosis among patients, comparing the sensitivity, specificity, positive and negative predictive value of the Selvester QRS score. A total of 112 patients from the Institute of Cardiology Dante Pazzanese outpatient clinic with hypertrophic cardiomyopathy were analyzed, and 75 of them were included. They were divided into two groups: ICD patients with 60 patients and no ICD with 15 patients. Clinical, echocardiographic, digital electrocardiography and computed tomography of the heart were collected. The Selvester score was calculated and the measurement and location of late enhancement in the tomographic sections of the patients were performed. The correlation of the results was analyzed by the linear regression. The most remarkable features and frequencies of the group were male gender 49.4%, age 41.63 ± 15.16 years, functional class I / II - NYHA 90.6%, atrial fibrillation 21.3%, low prevalence of comorbidities as hypertension 37.3%, diabetes 4%, dyslipidemia 17.3%, creatinine clearance > 60mL/min in 100% and absence of known coronary artery disease, left ventricular ejection fraction preserved 69.9 ± 5.46, measured of the interventricular septum 21.04 ± 6.23 and prevalence of gradient > 30mmHg in the left ventricular outflow tract 37.3%. Classic risk factors as sudden family death and history of syncope were the most prevalent 57.3% each, the use of beta-blocker occurred in 89.3%. The mass of fibrosis by multidetector computed tomography was 9.87 ± 10.79g, representing a percentage of 5.66 ± 6.16, with a prevalence of 88% of the sample. Selvester QRS score, was found 8.44 ± 7.39 percent of fibrosis with a prevalence of 76%. In the kappa analysis for the categorical variable between the Selvester score and the computed tomography of the heart, we found a weak correlation r = 0.38 (p <0.01), as a continuous variable applying the linear regression, a strong correlation was found r = 0.7 (p <0.01). The sensitivity, specificity, positive predictive value and negative predictive value of the Selvester QRS score for the diagnosis of fibrosis were 84.8%, 88.8%, 98.2% and 44.4%, respectively. The location of the fibrosis showed weak correlation between the methods r = 0.16 (p <0.01). The results of this study indicate there is a moderate correlation between the Selvester QRS score and the late enhancement by multidetector computed tomography in the quantification of fibrosis in patients with hypertrophic cardiomyopathy.

FUNDAMENTOS: O polimorfismo e a atividade da enzima conversora da angiotensina (ECA) contribuem, de forma significante, na expressão fenotípica e no prognóstico de pacientes com cardiomiopatia. OBJETIVOS: Determinar o polimorfismo da ECA, realizar a sua dosagem sérica e correlacioná-los com o grau de hipertrofia miocárdica e o índice de massa do ventrículo esquerdo em pacientes com cardiomiopatia hipertrófica (CMH) nas formas familiar e não familiar. CASUÍSTICA E MÉTODO: Foram estudados 136 pacientes consecutivos com CMH (69 da forma familiar e 67 da forma não familiar) com média de idade de 40,53±17,45 anos, sendo 76 do sexo masculino. Os indivíduos foram submetidos ao ecocardiograma para obtenção das medidas do septo interventricular, parede posterior e massa do ventrículo esquerdo e coleta de sangue para determinação do polimorfismo e dosagem sérica da atividade da ECA. RESULTADOS: Quanto ao genótipo do polimorfismo do gene da ECA, encontramos DD 47(35%), ID 71(52%) e II 18 (13%), sendo que do genótipo DD 34% na forma familiar e 36% na forma não familiar. A média da atividade da ECA foi de 56.414±19.236 para os pacientes com CMH na forma familiar e de 55.085±22.634 para a forma não familiar (p = 0,714). A média do índice de massa do ventrículo esquerdo na forma familiar foi 154±63 g/m2 e na forma não familiar foi 174±57 g/m2 (p = 0,008). A média do septo interventricular nas formas familiar e não familiar foi, respectivamente, 19±5 mm e 21±5 mm (p = 0,020). A média da parede posterior do ventrículo esquerdo nas formas familiar e não familiar foi, respectivamente, 10±2 mm e 12±3 mm (p = 0,0001). Não observamos correlação entre o polimorfismo e o grau de hipertrofia miocárdica (p = 0,651). Houve correlação positiva entre a atividade da ECA e o índice de massa do ventrículo esquerdo (p = 0,038). Os pacientes com a forma familiar, pela curva de regressão logística, possuíam o risco de apresentar índice de massa maior ou igual 190 g/m2, somente com o dobro do valor da atividade da ECA, quando comparados aos pacientes com a forma não familiar (p = 0,022). CONCLUSÕES: Não houve diferença estatisticamente significante entre o genótipo do polimorfismo e da atividade da ECA nos pacientes com CMH nas formas familiar e não familiar. Não houve correlação entre o polimorfismo da ECA e o grau de hipertrofia miocárdica. Houve correlação positiva entre a atividade da ECA e o índice de massa do ventrículo esquerdo. / BACKGROUND: The polymorphism and the activity of the angiotensin converting enzyme (ACE) contributes of significant form in the phenotypic expression and the prognostic of patients with cardiomyopathy. OBJECTIVES: To determine the ACE polymorphism and ACE plasma levels in patients with hypertrophic cardiomyopathy (HCM) in the familial and nonfamilial forms and to correlate it with the degree of myocardium hypertrophy and with the left ventricular mass index. PATIENTS AND METHODS: 136 consecutive patients with HCM (69 of familial and 67 of nonfamilial forms) were studied. The mean age was 40.53±17.45 years, 76 were male. The individuals were submitted to the Echo-Doppler for the measurement of interventricular septum, wall thickness and the left ventricular mass index. The blood samples were taken for extraction of the DNA for the polymerase reaction and measurement of ACE plasma levels. RESULTS: Regarding the genotype of the ACE gene polymorphism, we found DD 47 (35%), ID 71 (52%) and II 18 (13%), being that of genotype DD 34% in the familial and 36% in the nonfamilial forms. The mean of the activity of the ACE was 56.414±19.236 for the patients with HCM in the familial form and 55.085±22.634 in the non familial form (p = 0.714). The mean of the left ventricular mass index in the familial form was 154±63 g/m2 and in the nonfamilial form was 174±57 g/m2 (p = 0.0080). The mean of interventricular septum in the familial and nonfamilial forms was 19±5 mm and 21±5 mm (p = 0.0200), respectively. The mean of the wall thickness in the familial and nonfamilial forms was 10±2 mm and 12±3 mm (p = 0.0001), respectively. We did not observe correlation between the polymorphism and the degree of myocardium hypertrophy (p = 0.651). A positive correlation between the activity of the ACE and the left ventricular mass index (p = 0.038) was observed. In patients with the familial form, using a logistic regression curve, they had the risk to present the left ventricular mass index >= 190 g/m2, only with the double of the value of the activity of the ACE, when compared with the patients in the nonfamilial form (p = 0.022). CONCLUSIONS: There was no difference between the patients with HCM in the familial and nonfamilial forms regarding genotype of the polymorphism and activity of the ACE. There was no correlation between the polymorphism of the ACE with the degree of myocardium hypertrophy. Positive correlation with the activity of the ACE and the left ventricular mass index was observed.

Introdução: O tratamento alternativo de Redução septal percutânea (RSP) em pacientes com cardiomiopatia hipertrófica obstrutiva é relativamente novo e há poucos trabalhos publicados sobre a evolução tardia. Objetivos: Avaliar nos pacientes com cardiomiopatia hipertrófica obstrutiva sintomáticos e refratários ao tratamento clínico, tratados com RSP, a sobrevida cardíaca e global, qualidade de vida, eventos maiores e as alterações encontradas no eletrocardiograma (ECG), ecocardiograma(ECO) e Holter 24h antes e na evolução tardia de até 15 anos. Método: Foram incluídos pacientes consecutivos que realizaram RSP no Instituto Dante Pazzanese de Cardiologia e no Hospital do Coração de Outubro de 1998 até junho de 2013. Todos os pacientes realizaram exame clínico, ECG e ECO, e a maioria Holter 24h e responderam o questionário DASI antes e pós-RSP. Os dados qualitativos foram descritos em frequências absolutas e relativas e os quantitativos resumidos em médias ± desvios padrão. Para as variáveis quantitativas foram utilizados modelos ANOVA com medidas repetidas, seguidos pelo método de comparações múltiplas de Bonferroni. O nível de significância de 0,05 foi aceito. Resultados: Dos 56 pacientes incluidos, 28 (50%) eram homens, a idade média foi 53,2 ±15,5 anos sendo 2 crianças e 11 (19,6%) tinham coronariopatia. A maioria estava em classe funcional III-IV, o gradiente médio basal por ECO foi 92,8 ± 3,3 mmHg, a espessura do septo 23,9 ± 0,6 e 62,5% tinha insuficiência mitral (IM) moderada. Durante a internação 1 (1,7%)paciente implantou marcapasso. Durante o seguimento de 7,4 ± 4 anos ocorreram 3 implantes de CDI, 2 por prevenção secundaria e 1 marcapasso, 1 nova RSP, 3 cirurgias de miectomias e houve 7 (12,5%) óbitos, apenas 2 de causa cardíaca. O tempo médio de sobrevida, estimado pelo método de Kaplan Meier foi de 13,3 anos (IC95% 12,2 a 14,5 anos), com expectativa de sobrevida de 96,4% em 1 ano, 87,7% em 5 anos e 81,0% a os 12 anos pós-RSP. Houve melhora significativa na qualidade de vida pelo questionário DASI e na classe funcional da NYHA que passou de 3,6 ± 0,5 para 1,2 ± 0,5 no pós-RSP. Na última avaliação do ECO o gradiente 9,37 ± 6,7 mmHg, o septo 12,87 ± 0,98 mm e a IM foi discreta em 90% todos com p < 0,001. Das variáveis analisadas somente o gradiente no estresse, p=0,039 e a massa p=0,024 foram associados a pior prognóstico. Conclusões: A redução septal percutânea mostrou, na evolução tardia com 100% de seguimento, ser uma técnica segura, eficaz em manter os benefícios tardiamente com baixa mortalidade, oferecendo melhora significativa da classe funcional e da qualidade de vida para os pacientes. / Introduction: Percutaneous septal Reduction (PSR) is a relatively new alternative treatment in patients with obstructive hypertrophic cardiomyopathy and there are few published studies on late evolution. Objectives: Evaluate in symptomatic patients with hypertrophic obstructive cardiomyopathy refractory to medical treatment and who underwent PSR, cardiac and overall survival, quality of life, major events and changes found on the electrocardiogram (ECG), echocardiography (ECHO) and Holter 24h before and after PSR during an evolution up to 15 years. Method: Consecutive patients who were submitted to RSP in Dante Pazzanese Institute of Cardiology and Heart Hospital from October 1998 were included. All patients went through clinical, ECG and ECHO examination, and nearly all answered DASI questionnaire, 24-hour Holter monitoring before and after PSR. Qualitative data were described as absolute and relative frequencies and quantitative summarized as means ± standard deviations. ANOVA models were used for quantitative variables with repeated measures, followed by Bonferroni method for multiple comparison. Significance level of 0.05 was accepted. Results: From 56 patients included, 28 (50%) were men , the mean age was 53.2 ± 15.5 years with 2 children and 11 (19.6%) had coronary artery disease . Most were in functional class III - IV from NYHA, the mean baseline ECO gradient was 92.8 ± 3.3 mmHg, the septal thickness 23.9 ± 0.6mm and 62.5 % had moderate mitral regurgitation (MR). During hospitalization 1 (1.7%) patient required permanent pacemaker. During follow-up of 7.4 ± 4 years, 3 patient required ICD implantation, 2 (for secondary prevention), 1 permanent pacemaker, 1 new RSP, 3 myectomy surgery. There were 7 (12.5%) deaths but only 2 of cardiac causes. The median survival time estimated by the Kaplan Meier was 13.3 years (95% CI 12.2 to 14.5 years), with expected survival of 96.4% at 1 year, 87.7% at 5 years and 81.0% at 12 years post-PSR. Significant improvement was seen in quality of life inferred by DASI questionnaire answers and NYHA functional class from 3.6 ± 0.5 to 1.2 ± 0.5. In last evaluation we found statistical significant reduction in ECO gradient 9.37 ± 6.7 mmHg, septum thikness 12.87 ± 0.98 mm and MR was mild in 90 % of patients. Of the variables analyzed only stress gradient (p = 0.039) and mass (p = 0.024) were associated with worse prognosis. Conclusions: The results of this study suggest that percutaneous septal reduction in late evolution with no loses in follow-up, is a safe technique, effective in reducing ventricular gradient and preserving the benefits in long-term evolution with low mortality, offering significant improvement in functional class and quality of life for patients.

INTRODUÇÃO: A ecocardiografia tridimensional em tempo real (E3DTR) vem provando sua acurácia para quantificar os volumes do ventrículo esquerdo (VE), fração de ejeção (FEVE) e massa em pacientes com cardiomiopatia. Na cardiomiopatia hipertrófica (CMH), onde a morfologia ventricular pode estar muito alterada, a análise das estruturas cardíacas é fundamental para indicação da terapêutica ideal. A ressonância magnética cardiovascular (RMC) é um método superior na análise segmentar do VE em comparação a ecocardiografia bidimensional (E2D), mas com alta complexidade e existente em poucos centros diagnósticos, com contraindicações e limitações para a sua realização. MÉTODOS: Estudo transversal, comparativo, duplo cego, em 20 portadores de CMH, com E2D, E3DTR e RMC realizados com intervalo máximo de 06 meses e armazenados em formato digital. A espessura das paredes, volumes, função sistólica e massa ventricular esquerda foram analisados pelos métodos ecocardiográficos e pela RMC, assim como o movimento anterior sistólico da valva mitral, o índice geométrico do VE e o índice sistólico de dissincronia do VE. ANÁLISE ESTATÍSTICA: Análise estatística pelo coeficiente de concordância de Lin, correlação linear de Pearson e modelo de Bland-Altman. RESULTADOS: Foi obtida exeqüibilidade elevada acima de 94%, dependente do parâmetro avaliado. Concordância satisfatória e forte correlação linear evidenciada para a análise segmentar (Rc>0.84 e r>0.85; p<0.0001) observada para os métodos ecocardiográficos comparados à RMC, com concordância excelente entre os métodos ecocardiográficos (Rc=0,92 e r=0,92, p<0,0001). Concordância satisfatória e forte correlação linear para a fração de ejeção do VE (Rc=0.83 e r=0.93; p<0.0001) pela E3DTR comparada à RMC. Concordância excelente e forte correlação linear para o VDFVE e VSFVE pela E3DTR comparada à RMC e pela E2D comparada à E3DTR (Rc>0.90 and r>0.95; p<0.0001), assim como para a massa do VE, para os métodos E3DTR e RMC (Rc=0.96 e r=0.97; p<0.0001). Evidenciada maior exeqüibilidade da análise do MAS pela E3DTR. O índice geométrico do VE foi >0,15mmxm²xml-1 para todos os métodos. Observada correlação negativa entre o índice de dissincronia do VE e o percentual de fibrose miocárdica, sem significância estatística. CONCLUSÕES: A E3DTR é precisa e superior à E2D na avaliação da distribuição da hipertrofia miocárdica, quantificação dos volumes, função e massa ventricular esquerda em pacientes com CMH quando comparada à RMC, e parece ser superior na análise do MAS, pela melhor visão espacial da valva mitral.Todas as medidas do índice geométrico do ventrículo esquerdo estavam acima de 0,15mmxm²xml-1, compatível com CMH. Não foi identificada correlação entre o índice sistólico de dissincronia ventricular esquerda e a fibrose miocárdica. / INTRODUCTION: Real-time three-dimensional echocardiography (RT3D) has been demonstrated an accurate technique for the quantification of left ventricular (LV) volumes, ejection fraction (LVEF), and mass. In patients with hypertrophic cardiomyopathy (HCM), in which alterations of ventricular morphology are common, cardiac structural analysis is of utmost importance for guiding adequate therapy. Although magnetic resonance imaging (MRI) seems to have better definition for segmental analysis than two-dimensional echocardiography, (2D-E), it is considered a complex test with low availability and some limitations for use. METHODS: Comparative and double-blinded study in 20 patients with HCM. All patients underwent 2DE, RT3D and MRI within maximal interval of 6 months. Parameters analyzed by echocardiography and MRI included: wall thickness, LV volumes, systolic function, LV mass, systolic anterior motion of mitral valve, LV geometric index and LV dyssynchrony index. Statistical analysis was performed by Lin agreement coefficient, Pearson linear correlation and Bland-Altman model. RESULTS: Feasibility for measurements by MRI and echocardiography was 94%. There was good agreement and linear correlation between segmental analysis by echocardiography and MRI (Rc>0.84 and r>0.85; p<0.0001) and excellent correlation between 2DE and RT3DE (Rc=0.92 and r=0.92; p<0.0001). We also observed good agreement and linear correlation between RT3DE and MRI for ejection fraction (Rc=0.83 and r=0.93; p<0.0001) and excellent agreement and linear correlation between RT3DE and MRI for LV end diastolic volume and LV end systolic volume determinations (Rc>0.90 and r>0.95; p<0.0001) and mass (Rc=0.96 and r=0.97; p<0.0001). The feasibility for systolic anterior motion of mitral valve was higher by RT3DE (91%) than 2DE (64%). LV geometric index was >0.15 mmxm²xml-1 for all techniques. There was no correlation between LV dyssynchrony index and the percentage of myocardial fibrosis. CONCLUSIONS: RT3D is an accurate technique with superior performance than 2DE for the evaluation of myocardial hypertrophy localization, LV volume and functional determination as well as for LV mass assessment in patients with HCM in comparison with MRI. In addition, it seems to be superior for the analysis of systolic anterior motion due to its better spatial view of mitral valve. All measurements of LV geometric index were above the value of 0.15 mmxm²xml-1, and such findings are compatible with HCM. No correlation between LV dyssynchrony index by RT3D and the percentage of myocardial fibrosis determined by MRI was identified.

Die hypertrophe Kardiomyopathie ist eine autosomal dominant vererbte Herzmuskelerkrankung. Es kommt zu einer asymmetrischen Hypertrophie insbesondere des Herzmuskels. Symptome sind unspezifisch und reichen von Dyspnoe bis hin zu Synkopen. Gelegentlich ist der plötzliche Herztod die erste Manifestation der Erkrankung. Molekulargenetische Untersuchung des Genomes dieser Patienten zeigten, dass diese Patienten Mutationen im Proteinen des Sarkomers aufwiesen. Hierunter fällt das beta-MHC-Gen und alpha-Tropomysin-Gen. Wir untersuchten 45 nicht miteinanderverwandte Patienten auf Mutationen im beta-MHC-Gen und im alpha-Tropomysin-Gen. Folgende molekulargenetische Untersuchungen wurden angewendet: Polymerase-Ketten-Reaktion, Single-Strand-Polymorphismus-Anlyse und Sequenzierung. Bei 6 Patienten (13%) fanden wir eine Mutation im beta-Myosin-Gen. Kein Patient hatte eine Mutation im alpha-Tropomyosin-Gen. In der Literatur wird eine Mutation im beta-MHC-Gen in bis zu 35% und im alpha-Tropomyosin-Gen in bis zu 3% der Fälle angenommen. Unsere Patienten hatten die Mutationen: Exon 13 Arg403Trp und Val411Ile, Exon 19 Arg719Trp, Exon 20 Ile736Thr, Exon 21 Leu796Phe und Exon 23 Cys905Phe. Die Mutationen Arg403Trp und Arg719Trp waren vorher bereits bekannt. Die Mutationen, Ile736Thr, Val411Ile, Leu796Phe und Cys905Phe wurden in der Form von uns erstmals ermittelt. Offensichtlich besitzen unsere Patienten überdurchschnittlich häufiger Mutationen in anderen Genen, die in dieser Studie nicht untersucht wurden. Der Phänotyp der Krankheit der HCM war bei unserem Patientenkollektiv sehr heterogen, und es ließen sich keine signifikanten Unterscheidungen eststellen. So haben wir uns darauf beschränkt, bei den 6 Patienten mit Mutationen nur nach den von Burn et al. (1997) aufgestellten Risikofaktoren zu suchen, die einen plötzlichen Herztod herbeiführen können, und haben sie danach in Patienten mit einem höheren oder niedrigeren Risiko eingestuft. Kriterien für ein erhöhtes Risiko, einen plötzlichen Herztod zu erleiden, wurden von Patienten mit den Mutationen: Exon 13 Arg403Trp, Exon 13 Val411Ile, Exon 19 Arg719Trp, Exon 20 Ile736Thr und Exon 21 Leu796Phe erfüllt. Mutationen an diesen Positionen sind auch in der Literatur mit einem erhöhten Risiko für einen plötzlichen Herztod assoziiert worden. Der Patient mit der Mutation im Exon 23 Cys905Phe wies wenige Risikofaktoren auf und unterscheidet sich somit nicht von den in der Literatur beschriebenen Patienten. Wir konnten dies mit unseren Ergebnissen bestätigen. / Hypertrophic Cardiomyopathy is disease of the cardiac muscle which results in an asymmetric hypertrophy especially of the interventricularseptum of the heart. It is transmitted in an autosomal dominant way. The symptoms are unspecific reaching from dyspnoe to syncopes. Sometimes the sudden death is the first manifestation of the disease. Molekular genetic researches showed that in the patients genes Mutations in proteins of the sarkomer were detectable. Two of them are alpha-Tropomyosin and beta-Myosin Heavy Chain. We examined 45 unrelated Patient of the existence of Mutations in alpha-Tropomyosin and beta-Myosin Heavy Chain. We used following Examinations: PCR, SSCP, Sequencing. A mutation in the beta-Myosin Heavy Chain were found in 6 Patients (13%), non in alpha-Tropomyosin. Generally mutations are expected in 35% in beta-Myosin Heavy Chain and 3% in alpha-Tropomyosin. Our patients seem to have mutations in genes we did not examine in this study. We detected Mutations in: Exon 13 Arg403Trp and Val411Ile, Exon 19 Arg719Trp, Exon 20 Ile736Thr, Exon 21 Leu796Phe und Exon 23 Cys905Phe. Mutation Arg 403Trp and Arg719Trp have been known in this form before, the others were new. As the phenotypes of our patients were heterogenous and not significantly to be distinguished we looked for risk factors for sudden death as described by Burn et al. 1997 within our group of patients with mutations. Five Persons showed risk factors as discribed: Exon 13 Arg403Trp and Val411Ile, Exon 19 Arg719Trp, Exon 20 Ile736Thr, Exon 21 Leu796Phe. The person with the mutation Exon 23 Cys905Phe showed no risk factors for sudden death. Our results correlate with those of earlier studies. The patient with the mutation Exon 23 Cys905Phe was classified as a low risk patient while the other mutations correlate with a further high risk.

Estudos epidemiológicos e experimentais tem mostrado consistentemente que tanto as exposições agudas e crônicas à poluição do ar estão associadas com uma variedade de doenças cardiovasculares. A poluição atmosférica é composta por uma mistura de substâncias nocivas incluindo partículas e gases. Os efeitos adversos cardiovasculares são mais comumente atribuídos às partículas e experimentos toxicológicos tem demonstrado diferentes mecanismos pelos quais a exposição às partículas pode provocar estes efeitos. Neste estudo nos investigamos os efeitos do tempo (7, 15 e 21 dias) de exposição as partículas ambientais (dose = 600 g/m³) nos parâmetros funcionais e morfológicos do coração de ratos normais e ratos com hipertrofia ventricular esquerda (HVE) induzida pelo isoproterenol (agonista não seletivo -adrenérgico de ação direta) (1,2 mg/kg). A utilização de ratos com HVE foi motivado pelo fato de que a existência de uma doença cardiovascular prévia representa um fator de risco elevado para estes indivíduos. Nossos dados mostraram que o tempo de exposição ao material particulado concentrado é um fator importante para a magnitude dos efeitos sobre a função e morfologia do coração, como mostrado pelo aumento da variabilidade da frequência cardíaca, diminuição da frequência cardíaca e aumento no volume de tecido conjuntivo no miocárdio do ventrículo esquerdo. Os ratos com HVE mostraram efeitos similares, porém mais graves sobre o coração, que incluíram diminuição da pressão arterial e aumento da hipertrofia dos cardiomiócitos em comparação com ratos com HVE não expostos. Concluindo, nossos resultados corroboram com achados anteriores que mostram que a poluição atmosférica particulada induz alterações no controle autonômico do coração e que indivíduos com doenças cardiovasculares preexistentes são mais afetados que indivíduos normais. Mostramos ainda que o material particulado concentrado é capaz de induzir alterações na microestrutura do miocárdio, dependendo da dose acumulada de exposição / Epidemiological and experimental studies have consistently shown that both short- and long-term exposures to air pollution are associated with a variety of cardiovascular diseases. Air pollution is composed by a mixture of noxious substance including particles and gases. The cardiovascular adverse effects are more commonly attributed to particles and toxicological experiments have demonstrated several mechanisms by which particle exposure may trigger these effects. In this study we investigated the effects of time (7, 15 and 21 days) of exposure to concentrated ambient particles (dose = 600 g/m³) on morphofunctional parameters of the heart in normal and rats with left ventricular hypertrophy (LVH) induced by isoproterenol (nonselective -adrenergic agonist with direct action) (1.2 mg/kg). The use of LVH rats was motivated by the fact that individuals with cardiovascular diseases are considered at higher risk for effect of ambient PM. Our data have shown that time is an important factor on the magnitude of the effects of concentrated ambient particles on heart function and morphology, as shown by increased HRV (heart rate variability), decreased heart rate and increased volume of connective tissue in left ventricle myocardium. LVH rats presented similar outcomes but more severe effects on the heart which included decreased blood pressure and increased cardiomyocyte hypertrophy compared to non-exposed LVH rats. In conclusion, our results corroborate with previous findings that particulate air pollution induces changes in the autonomic control of the heart and that individual with previous cardiovascular disease are more affected than normal ones. We have further shown that concentrated ambient particles are capable of inducing changes in the microstructure of the myocardium depending on accumulated dose of exposure

A estratificação de risco para morte súbita em pacientes com cardiomiopatia hipertrófica ainda é um desafio. Sua prevenção pelo cardiodesfibrilador automático é eficaz, porém, onerosa e não isenta de riscos. Pacientes com indicação de cardiodesfibrilador automático para prevenção primária, baseada em fatores de risco clínicos, apresentam baixa taxa de terapias apropriadas. Estudos que validem novos fatores de risco são necessários, visando identificar pacientes com maior probabilidade de morte súbita e, portanto, que se beneficiam do implante do dispositivo. Estudos que correlacionam a presença de realce tardio com arritmias ventriculares e morte súbita foram realizados, entretanto, sua aplicabilidade clinica ainda não é consenso. Objetivos: Avaliar, em portadores de cardiomiopatia hipertrófica, se a presença e a extensão de realce tardio, identificado pela tomografia computadorizada, correlaciona-se com a ocorrência de taquiarritmias ventriculares registradas no monitor de eventos do cardiodesfibrilador automático, durante um seguimento clínico ambulatorial. Métodos: Foram incluídos pacientes com cardiomiopatia hipertrófica dos ambulatórios de Eletrofisiologia e Miocardiopatias do Instituto Dante Pazzanese de Cardiologia. Os pacientes foram divididos em dois grupos: grupo I composto por aqueles que receberam terapia apropriada pelo cardiodesfibrilador automático ou tiveram apenas a documentação de taquicardia ventricular não sustentada pelo cardiodesfibrilador automático; grupo II, composto por pacientes sem documentação de arritmias ventriculares no monitor de eventos. As variáveis contínuas foram comparadas utilizando-se testes t de Student pareado ou Wilcoxon; para as categóricas o teste do x2. Para análise dos dados, utilizou-se o programa SPSS. Valores de p < 0,05 foram considerados estatisticamente significativos. Resultados: Sessenta e um pacientes (idade média 39±15 anos, 51% mulheres, com seguimento médio 5,13±3,0 anos) foram avaliados. Em 91,8%, a indicação do cardiodesfibrilador automático foi por prevenção primária. Durante o seguimento clínico, cinco pacientes (8,2%) apresentaram terapias apropriadas e 15 (24,6%) tiveram taquicardia ventricular não sustentada, mas sem terapia. A densidade de fibrose (incluindo massa de ventrículo esquerdo acometida e percentual de acometimento) não foi estatisticamente diferente entre os grupos I e II (4,3±4,8% vs 7,0±7,7% nos grupos I e II, respectivamente, p = 0,13). Entretanto, 85% dos pacientes com taquicardia ventricular apresentavam fibrose à tomografia computadorizada. Maiores densidades de fibrose se correlacionaram com idades mais jovens, com menores frações de ejeção e sexo masculino. Espessura septal >= 30mm se correlacionou à maior massa de fibrose. Houve correlação entre o surgimento de fibrilação atrial e maior porcentual de fibrose do ventrículo esquerdo. Dentre os fatores que se correlacionaram com maior densidade de fibrose, nenhum deles se correlacionou com eventos arrítmicos ventriculares. A associação dos fatores clínicos ou fatores clínicos isolados que motivaram a indicação do implante do cardiodesfibrilador automático não se correlacionou com eventos arrítmicos. Os pacientes do grupo I apresentaram maior diâmetro diastólico do ventrículo esquerdo e maior diâmetro do átrio esquerdo quando comparado com os pacientes do grupo II (47,7±4,7mm vs 43.1±5,4 mm, p = 0,002 e 47,8±8mm vs 41,5±7,1mm, p = 0,003, respectivamente). Conclusões: 1. A presença de fibrose detectada pela tomografia computadorizada apresenta razoável sensibilidade para identificação de pacientes com risco para taquicardia ventricular; 2. A densidade de fibrose foi similar nos pacientes dos grupos I e II; 3. Pacientes com fibrilação atrial apresentaram maior densidade de fibrose ventricular detectada pela tomografia computadorizada em comparação aos pacientes sem fibrilação atrial; 4. O diâmetro diastólico final de ventrículo esquerdo e o diâmetro atrial esquerdo associaram-se à maior risco de taquicardia ventricular; 5. Os fatores de risco convencionais, associados ou não à fibrose, não se correlacionaram com maior probabilidade de ocorrência de eventos arrítmicos ventriculares. / Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy patients is still challenging. Primary prevention of sudden death with implantable cardioverter-defibrillator is an effective, however, costly and not risk-free method. Patients with implantable cardioverter-defibrillator indicated for primary prevention based on clinical risk factors display low rates of appropriate therapies. Studies evaluating new risk factors are needed seeking to identify who would be mostly at risk of sudden cardiac death, and therefore benefit from cardioverter-defibrillator. Studies have been conducted to establish a correlation between late enhancement and ventricular arrhythmias and sudden cardiac death; however, its clinical applicability is still controversial. Objective: To evaluate if the presence and extension of late enhancement, identified by computed tomography, correlates with the occurrence of ventricular arrhythmias in hypertrophic cardiomyopathy patients. Methods: Patients with hypertrophic cardiomyopathy followed in Electrophysiology and Cardiomyopathies divisions at Dante Pazzanese Institute of Cardiology were included in the study. Patients were divided into two groups: group I composed by those with appropriate therapies (shock or overdrive) or non-sustained ventricular tachycardia; and group II, composed by patients without documented ventricular arrhythmias. Continuous variables were compared using paired t-student test or Wilcoxon test. Categorical variables were analyzed using chi-square test. For data analysis, the SPSS program was used. P values < 0.05 were considered statistically significant. Results: Sixty one patients (mean age 39 ± 15 years, 51% female, average follow up 5.13 ± 3 years) were evaluated. In 91.8%, cardioveter-defibrillator was indicated by primary prevention. During the follow up, five patients (8.2%) had appropriate therapies and 15 (24.6%) presented non-sustained ventricular tachycardia without therapies. Fibrosis density, (including left ventricular mass compromise and percentage) was not statistically different between the groups (4.3±4.8% for group I vs. 7.0±7.7% for group II, p =0.13). However, 85% of patients with ventricular tachycardia had fibrosis on cardiac computed tomography. Larger fibrosis density correlated with younger age, reduced ejection fraction and male gender. Septum >30 mm correlated with fibrosis mass. There was a correlation between atrial fibrillation and higher left ventricular fibrosis percentage. Among the factors that correlated with higher fibrosis density, none of them had correlation with ventricular arrhythmic events. The combination of clinical factors that motivated the implantation of cardioverter-defibrillator did not correlate with arrhythmic events. Patients at group I had larger left ventricular diastolic diameter (47.7±4.7 vs. 43.1±5.4mm, respectively, p= 0.002) and left atrium diameter (47.8±8.2 vs. 41.5±7.1 mm, respectively, p=0.003). Conclusions: 1. The presence of fibrosis detected by cardiac tomography had reasonable sensitivity to identify patients at risk of ventricular tachycardia; 2. Fibrosis density was similar between groups I and II; 3. Patients with atrial fibrillation had more fibrosis density detected by cardiac tomography compared to patients without atrial fibrillation; 4. Left ventricular end diastolic diameter and left atrial diameter correlated with increased risk of ventricular tachycardia; 5. Classical risk factors, associated or not with fibrosis, did not correlate with increased probability of ventricular arrhythmic events.

FUNDAMENTOS: Na cardiomiopatia hipertrófica (CMH) a disfunção diastólica do ventrículo esquerdo (VE) é causada por hipertrofia dos miócitos e fibrose intersticial. A Angiotensina II (Ang II) pode promover hipertrofia, fibrose e alteração de relaxamento miocárdico. Na hipertrofia secundária a hipertensão o bloqueio dos receptores tipo 1 (AT1) da Ang II diminui a hipertrofia e a fibrose e, em animais com CMH losartan causou reversão da fibrose miocárdica. Os efeitos do antagonismo da Ang II na CMH humana não são conhecidos. OBJETIVOS: Avaliar os efeitos do losartan, um bloqueador dos receptores AT1 da Ang II, sobre a hipertrofia e a função diastólica do VE em pacientes com CMH não obstrutiva. CASUÍSTICA E MÉTODO: Foram estudados 27 pacientes consecutivos portadores de CMH na forma não obstrutiva, com média de idade de 34,4 anos, sendo 14 homens, que receberam losartan 100 mg/dia durante 6 meses. Antes do tratamento e ao final do mesmo foram avaliadas: a classe funcional (CF), a hipertrofia e a função diastólica do VE esquerdo pela ecocardiografia (modo-M, Doppler mitral, venoso pulmonar e Doppler tecidual do anel mitral) e a concentração plasmática do fragmento amino-terminal do pro-peptídeo natriurético tipo B (NT-proBNP). Valores bi-caudais de p<0,05 em testes pareados foram considerados estatisticamente significantes. v RESULTADOS: CF - dos 19 pacientes sintomáticos antes do tratamento, 8 (42%) tornaram-se assintomáticos (p=0,008). A CF média passou de 2,04±0,81 para 1,48±0,64 (p=0,0001). Doppler ecocardiografia - redução do diâmetro atrial esquerdo de 43,3±6,2 mm para 40,5±6,1 mm (p<0,0001), diminuição da velocidade da onda atrial reversa do fluxo venoso pulmonar de 36,4±9,7 cm/s para 32,2±6,2 cm/s (p=0,008), aumento da velocidade diastólica inicial (Ea) do anel mitral de 10,7±3,2 cm/s para 11,95±3,01 cm/s (p=0,004), aumento da razão Ea/Aa de 1,11±0,36 para 1,33±0,48 (p=0,009), e diminuição da razão E/Ea de 8,37±5,4 para 6,46±3,2 (p=0,004). Não ocorreram modificações nas espessuras parietais nem nos diâmetros do VE. NT-proBNP - diminuição do valor mediano de 652 pg/ml para 349 pg/ml, assim como dos quartis e dos valores máximo e mínimo (p=0,003). CONCLUSÃO: Em pacientes com CMH não obstrutiva o antagonismo da angiotensina II com losartan 100 mg/dia durante 6 meses resultou em melhora bioquímica e da função diastólica do VE, sem evidente regressão de hipertrofia ao ecocardiograma. Esses resultados são promissores e indicam possíveis benefícios que podem ser obtidos com medicamentos que atuam inibindo o sistema renina-angiotensina em pacientes com CMH. / BACKGROUND: In hypertrophic cardiomyopathy (HCM) diastolic dysfunction of the left ventricle (LV) is caused by myocite hypertrophy and interstitial fibrosis. Angiotensin II (Ang II) has trophic and profibrotic effects on the heart, and may impair myocardial relaxation. In hypertensive LV hypertrophy Ang II type 1 (AT1) receptors blockade can reverse hypertrophy and fibrosis, and in animals with HCM, losartan reversed myocardial fibrosis. The effects of Ang II antagonism in humans with HCM are unknown. OBJECTIVES: To evaluate the effects of losartan, an AT1 blocker, in patients with non-obstructive HCM, with emphasis on LV diastolic function. PATIENTS AND METHODS: 27 consecutive patients, mean age 34.4 years, 14 males, were treated with losartan 100 mg/day during 6 months. Evaluations were performed at baseline and at 6 months, as follows: functional class (FC), left atrium diameter (LAD), LV hypertrophy and LV diastolic function (M-mode echocardiography, mitral flow and pulmonary venous flow Doppler, mitral annulus tissue Doppler), and plasma concentrations of the amino-terminal fragment of proBNP (NT-proBNP). RESULTADOS: FC - of the 19 symptomatic patients before the treatment, 8 (42%) were free of symptoms at 6 months (p=0.008). There were no changes in LV wall and cavity measures. LAD decreased from 43.3±6.2 mm to 40.5±6.1 mm (p<0.0001), and pulmonary venous atrial reverse velocity decreased from 36.4±9.7 cm/s to 32.2±6.2 cm/s (p=0.008). Tissue Doppler: mitral annulus early diastolic velocity (Ea) increased from 10.7±3.2 cm/s to 11.95±3.01 cm/s (p=0.004), Ea/Aa ratio increased from 1.11±0.36 to 1.33±0.48 (p=0.009), and E/Ea ratio decreased from 8.37±5.4 to 6.46±3.2 (p=0.004). NT-proBNP - there was a decrease in the median value from 652 pg/ml to 349 pg/ml, as well as a decrease in quartiles, maximum and minimum values (p=0.003). CONCLUSION: In patients with non-obstructive HCM, treatment with losartan 100 mg/day during 6 months resulted in Doppler echocardiographic and biochemical changes indicative of LV diastolic function amelioration, in the absence of evident LV hypertrophy regression. These preliminary results are promising and suggest that inhibition of the renin-angiotensin system may be benefic in human HCM

Background - Regular exercise reduces the risk of cardiovascular disease and subsequent sudden cardiac death (SCD). However, a small, but notable proportion of athletes die suddenly due to inherited or congenital disorders of the heart that predispose to malignant ventricular arrhythmias. Such tragedies are highly publicised, particularly when high-profile athletes are involved. To date, limited evidence for the efficacy of cardiovascular pre-participation screening exists outside of the Italian experience. Furthermore, limited data exists examining the impact of ethnicity on cardiac adaptations to physical training. Whilst the cardiovascular benefits of exercise are well known, the impact of life-long endurance exercise is less well understood. Long term high-intensity endurance exercise is associated with changes in cardiac morphology together with electrocardiographic alterations that are believed to be physiologic in nature. Recent data however, has suggested a number of deleterious adaptive changes in cardiac structure, function and electrical activity in response to life-long endurance activity. Aims and Objectives - The aims of this PhD were; 1) To find an effective preparticipation screening method that would successfully identify pre-existing cardiovascular abnormalities, 2) To identify the prevalence of hypertrophic cardiomyopathy and Long QT syndrome in elite UK athletes; 3) To examine the impact and significance of ethnicity upon left ventricular remodelling in elite athletes, and 4) To examine the acute and chronic impact of ultra-endurance exercise across the life-span in male endurance athletes. Major Results and Conclusions – 1) Study 2 sought to confirm the efficacy of resting 12-Lead ECG ‘alongside’ personal/family history questionnaires and physical examinations as collective tools to identify diseases that have the potential of causing sudden death within a cohort of elite junior athletes (n=1074) and physically active school children (n=1646). Nine participants were identified with a positive diagnosis of a disease associated with SCD. None of those diagnosed with a disease associated with SCD were symptomatic or had a family history of note. Thus, personal symptoms and family history questionnaires alone are inadequate in the identification of individuals with diseases associated with SCD. In conclusion, resting 12-Lead ECG is paramount when screening for diseases that have the potential of causing sudden death in the young. 2) Study 3 examined 3,500 asymptomatic elite athletes (75% male) with a mean age of 20.5 ± 5.8 years with 12-lead ECG and 2-dimensional echocardiography. None had a known family history of HCM. Of the 3,500 athletes, 53 (1.5%) had LVH (mean 13.6 ± 0.9mm, range 13 to 16mm), and of these 50 had a dilated LV cavity with normal diastolic function to indicate physiological left ventricular hypertrophy. Three (0.08%) athletes with LVH had a non-dilated LV cavity and associated deep T-wave inversion that could have been consistent with HCM. However, none of the 3 athletes had any other phenotypic features of HCM on further non-invasive testing and none had first-degree relatives with features of HCM. In conclusion, the prevalence of HCM in elite athletes is significantly less than in the general population; with the demands of strenuous exercise on the cardiovascular system selecting out most individuals with HCM. Study 4 examined 2000 elite athletes in order to identify the prevalence of Long QT syndrome. Three athletes had a QTc value of >500 ms and all exhibited one of: paradoxical prolongation of QTc during exercise, a confirmatory genetic mutation, or prolonged QTc in a first-degree relative. In contrast, none of the athletes with a QTc value of <500 ms had any other features to indicate LQTS. Accordingly, the prevalence of a prolonged QTc interval in elite British athletes is 0.4%. 3) Study 6 examined 300 nationally ranked UK black male athletes (mean age 20.5 years) in comparison to 150 black and white sedentary individuals and 300 highly-trained white male athletes. Black athletes exhibited greater LV wall thickness and cavity size compared with sedentary black and white individuals. Black athletes had greater LV wall thickness compared with white athletes. A minority of black athlete’s exhibit LVH ≥15 mm; proposing that in the absence of cardiac symptoms or a family history of HCM, an LV wall thickness ≥15 mm in black athletes may represent physiologic LVH when the LV cavity is enlarged and diastolic indexes are normal. 7 black athletes (12%) with LVH displaying deep T-wave inversions in leads V1 to V4. In conclusion, in the absence of obvious pathology, these electrical anomalies in black athletes likely represent a normal spectrum of ECG changes in response to physical training. 4) Study 8 examined 17 male participants (age 33.5 ± 6.5 years, 26–40 years) using cardiac magnetic resonance (CMR) and echocardiography before and after a marathon to investigate the relationship between systolic function and diastolic function against biomarkers of cardiac damage. Results demonstrates biomarkers of myocardial cell damage following an acute bout of prolonged exercise are not associated with either systolic or diastolic functional measures, and do not seem to be associated with any detectable myocardial inflammation, oedema, or scarring using either gold standard techniques of gadolinium enhanced CMR or echocardiography respectively. The impact of multiple episodes of prolonged exercise, as experienced by highly trained veteran endurance athlete is not fully understood. 5) Study 10 examined the cardiac structure and function of 12 life-long, competitive endurance veteran athletes (> 50 yrs, mean ± SD marathons 178 ± 209 (range 20 – 650)) against 17 young male endurance athletes (<40 yrs) using echocardiography and CMR with late gadolinium enhancement (LGE) to assess myocardial fibrosis. Lifelong veteran athletes had smaller LV and RV end-diastolic and end-systolic volumes (p<0.05) but maintained LV and RV systolic function compared with young athletes. In 6 (50%) of the veteran athletes LGE of CMR indicated the presence of myocardial fibrosis; no LGE in the young athletes. The prevalence of LGE in veteran athletes was not associated with the number of competitive marathons or ultra-endurance marathons (>50 miles) completed, age, LV and RV end-diastolic volumes or LV mass (p>0.05). In conclusion, there is limited evidence at present demonstrating that cardiovascular re-modelling following lifelong endurance exercise leads to long-term disease progression, cardiovascular disability or SCD.