Beatriz Piva e Mattos

Left ventricular function and endomyocardial biopsy in early and advanced dilated cardiomyopathy

We evaluated left ventricular function and endomyocardial biopsy in 20 patients with early and advanced dilated cardiomyopathy, with the purpose of assessing the correlation between histologic variables and systolic and diastolic filling indexes. Group 1 included 10 patients with no clinical history of heart failure and left ventricular ejection fraction > or = 45% and group 2, 10 patients with a clinical history of heart failure and left ventricular ejection fraction <45%. Group 1 showed lower left ventricular end-systolic and end-diastolic volumes indexes (49+/-14 versus 86+/-23 ml/m2, P<0.001; 98+/-25 versus 127+/-35 ml/m2, P=0.049), higher left ventricular ejection fraction (50+/-4 versus 32+/-4%, P<0.001) and lower coefficient of variation of percentage shortening of left ventricular transverse hemiaxes (0.3+/-0.1 versus 0.5+/-0.1, P=0.001) compared with group 2. Group 1 had higher A wave peak velocity (78+/-18 versus 60+/-20 cm/s, P=0.048), lower E/A ratio (0.9+/-0.3 versus 1.5+/-0.6, P=0.02) and slower E wave deceleration time (204+/-51 versus 155+/-50 ms, P=0.047) compared with group 2. Semiquantitative histologic scores did not differ significantly between groups. There was no significant correlation between histologic variables and left ventricular systolic and diastolic indexes. Thus, dilated cardiomyopathy shows borderline to severe left ventricular systolic impairment and distinct left ventricular diastolic filling abnormalities, according to the clinical stage. This study suggests a marked dissociation between histologic findings and functional abnormalities in early and advanced dilated cardiomyopathy.

Estratificação de risco para morte súbita na cardiomiopatia hipertrófica: bases genéticas e clínicas

A CMH manifesta-se por hipertrofia ventricular esquerda associada a desarranjo miofibrilar e fibrose intersticial, fatores que condicionam a disfuncao diastolica, isquemia miocardica e arritmias. O diagnostico preliminarmente baseado na deteccao clinica de formas com obstrucao da via de saida do ventriculo esquerdo (VE) evoluiu com o advento da ecocardiografia unie bidimensional a identificacao de hipertrofia predominante do septo interventricular3, caracteristica inicialmente destacada por Teare1. Estudos subsequentes evidenciaram o carater heterogeneo da doenca, no que se refere a extensao da hipertrofia4, apresentacao clinica, evolucao e prognostico57. Na ultima decada, a introducao da genetica molecular passou a constituir novo paradigma para o diagnostico da CMH, propiciando nao somente o melhor entendimento dos mecanismos envolvidos em sua patogenese, como tambem a individualizacao de distintos padroes de comprometimento anatomico e funcional.

Avaliação diagnóstica da cardiomiopatia hipertrófica em fase clínica e pré-clínica

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

Ventricular arrhythmias and left ventricular hypertrophy in hypertrophic cardiomyopathy

BACKGROUND In hypertrophic cardiomyopathy (HCM), the degree of left ventricular hypertrophy (LVH) could influence the development of ventricular arrhythmias. OBJECTIVE In HCM, analyze the association between the occurrence of ventricular arrhythmias determined by Holter electrocardiogram (ECG-Holter) and the degree of LVH determined by maximum wall thickness (MWT) in echocardiography and body mass index (BMI). METHODS Fifty-four consecutive patients with HCM underwent 24-hour ECG-Holter and echocardiography for assessment of level of LVH through MWT and BMI. Two levels were established for the occurrence of Ventricular Arrhythmias: I - alone or paired extrasystoles and II - Non- Sustained Ventricular Tachycardia (NSVT). RESULTS In 13 patients (24%) with NSVT (level II), there was a higher frequency of MWT of the left ventricle (LV) > 21 mm (n = 10, 77%, 25 ± 4 mm) and LLLV = 144 g/m² (n = 10, 77%, 200 ± 30 g/m²), in comparison with those presenting with extrasystole arrhythmias (level I) (n = 41, 76%), in which these measures were identified in, respectively, 37 % (n= 15, 23 ± 1 mm), p = 0.023, and 39% (n = 16, 192 ± 53 g / m²) of the cases (p = 0.026). The cut-off values mentioned were determined by the ROC curve with a confidence interval of 95%. NSVT was more common in patients with MWTLV > 21 mm and LLLV > 144 g/m² (8 of 13, 62%) than in those with (4 of 13, 31%) or without (1 of 13; 8%) echocardiographic variables above cut-off values (p = 0.04). CONCLUSION In HCM, occurrence of ventricular arrhythmias by Holter was associated with the degree of LVH assessed by echocardiography through MWT and BMI.

O diagnóstico da obstrução da via de saída do ventrículo esquerdo na cardiomiopatia hipertrófica

Hypertrophic cardiomyopathy is a prevalent genetic disease characterized by left ventricular hypertrophy, presenting dynamic obstruction of outflow tract with subaortic gradient happening at rest in 30% of the cases. It is attributed to the intricate interaction between the anterior mitral leaflet, the interventricular septum and altered flow vectors generated in left ventricle along with changes in outflow tract geometry. Mitral regurgitation in varying degrees is found with or without association with structural deformities of the valve apparatus. The exercise echocardiogram evidences latent obstruction easily induced by exercise in 60 to 75% of non-obstructive forms. The determination of the gradient under this condition must be considered in routine investigation of patients with mild or no obstruction at rest. The evaluation of hypertrophic cardiomyopathy incorporates methods based on the ultrasound image, which, along with MRI, allow recognizing ventricular obstruction generating mechanisms, thus facilitating the diagnosis and management of obstructive and latent obstructive forms.

Prevalence and Phenotypic Expression of Mutations in the MYH7, MYBPC3 and TNNT2 Genes in Families with Hypertrophic Cardiomyopathy in the South of Brazil: A Cross-Sectional Study

Background: Mutations in sarcomeric genes are found in 60-70% of individuals with familial forms of hypertrophic cardiomyopathy (HCM). However, this estimate refers to northern hemisphere populations. The molecular-genetic profile of HCM has been subject of few investigations in Brazil, particularly in the south of the country. Objective: To investigate mutations in the sarcomeric genes MYH7, MYBPC3 and TNNT2 in a cohort of HCM patients living in the extreme south of Brazil, and to evaluate genotype-phenotype associations. Methods: Direct DNA sequencing of all encoding regions of three sarcomeric genes was conducted in 43 consecutive individuals of ten unrelated families. Results: Mutations for CMH have been found in 25 (58%) patients of seven (70%) of the ten study families. Fourteen (56%) individuals were phenotype-positive. All mutations were missense, four (66%) in MYH7 and two (33%) in MYBPC3. We have not found mutations in the TNNT2 gene. Mutations in MYH7 were identified in 20 (47%) patients of six (60%) families. Two of them had not been previously described. Mutations in MYBPC3 were found in seven (16%) members of two (20%) families. Two (5%) patients showed double heterozygosis for both genes. The mutations affected different domains of encoded proteins and led to variable phenotypic expression. A family history of HCM was identified in all genotype-positive individuals. Conclusions: In this first genetic-molecular analysis carried out in the south of Brazil, we found mutations in the sarcomeric genes MYH7 and MYBPC3 in 58% of individuals. MYH7-related disease was identified in the majority of cases with mutation.

Genetic Bases of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is characterized by myofibrillar derangement and predominant hypertrophy of the interventricular septum associated with a reduced or normal left ventricular cavity . It determines diastolic dysfunction and a tendency towards myocardial ischemia, arrhythmia, and sudden death. With a prevalence of 1 case per 500 individuals , it occurs in all age groups, from birth to the 8 decade, having a genetic origin preliminarily detected from familiar forms among carriers of the disease . The complex character of this entity outlined in the first reports of the modern era 4,5 became unequivocally evident by systematic studies developed over recent decades . The application of a methodology generated in molecular genetics by obtaining genetic maps of high resolution facilitated the redefinition of concepts related to the pathology, physiopathology, and diagnosis of hypertrophic cardiomyopathy. Genetic analysis facilitating identification of the disease in its preclinical phase and risk stratification based on molecular criteria render the future introduction of genetic therapy viable. Hypertrophic cardiomyopathy has highly heterogeneous morphological, functional, and clinical characteristics. The phenotype is composed of ventricular hypertrophy associated with myofibril disorganization. Marked phenotype variation relative to the magnitude and extension of the myocardial hypertrophy is observed. Echocardiographic evaluation reveals predominant hypertrophy of the intraventricular septum of diffuse character, commonly extending to the free anterior-lateral wall of the left ventricle . Wall thickness is usually above 20mm, although measurements between 20 and 15mm have been found . Borderline thicknesses of 15mm or even 13mm have also been identified . Asymmetric forms predominate over concentric ones, representing 1 to 2% of the cases . Myofibrillar disarray extends over 5 to 30% of the myocardial tissue and has a low correlation with the degree of hypertrophy . Hypertrophic cardiomyopathy can appear without showing its main morphological characteristics. Arrhythmias and sudden death in the absence of echocardiographic signals of left ventricular hypertrophy (LVH) in patients with the genotype, indicate incomplete phenotype expression . It is concluded that the phenotype is represented by a continuous spectrum, from macroscopically normal to severe forms showing massive myocardial hypertrophy . The phenotype changes with age. Hypertrophic myopathy can appear at birth showing serious obstructive forms with marked hypertrophy, rapid evolution to cardiac failure, and a high level of mortality . It more frequently manifests clinically in adolescence when a detectable increase in parietal thickness of the left ventricle accompanies an increase in weight and stature . Although clinical evolution in children and adolescents is usually benign, annual mortality can reach 4.8%, higher than that shown among adults . Adolescents and young adults can manifest extreme degrees of LVH with outflow tract obstruction, cavity reduction, and evolution towards sudden death . An inverse relationship between age group and left ventricular parietal thickness may be shown . Gradual regression in hypertrophy, increased ventricle volume, and diastolic dysfunction occur in approximately 10% of individuals reaching maturity . Late forms, manifest after 65 years of age, are individualized, with a hypertrophy generally restricted to the interventricular septum . The natural history is also heterogeneous. While some cases remain in asymptomatic form indefinitely, other patients experience sudden death or evolve to cardiac failure. Although annual mortality recorded at reference centers falls between 2 and 6% , measurements among less selected populations fall between 0.5 and 1.5% of cases . Clinical indicators like degree of hypertrophy, records of ventricular arrhythmia, and abnormal response to exercise, have a limited value for risk stratification of sudden death .

Cellular and biomolecular mechanisms in dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a primary myocardial disease, characterized by unior biventricular dilation associated with a generally progressive contractile dysfunction . It is predominantly diagnosed in the advanced stage, in which it manifests itself by cardiomegaly and heart failure, causing significant morbidity and mortality . Less frequently, it is identified in the initial stage, in which the congestive signals are absent but ventricular dilation and dysfunction in a mild or moderate degree are evident . At first, DCM was considered a disease of obscure etiology. Several decades after being identified as an entity, its complex pathogenesis has gradually become better understood. Systematic studies generated in immunology, genetics, and cellular and molecular biology have contributed to the understanding of the disease mechanism. However, the heterogeneous character of DCM, coupled with the multiplicity of pathologic processes involved, has made this task difficult. DCM is currently understood as a multifactorial disease, in which viral infections, immunologic mechanisms and genetic factors, acting individually or together, result in a definitive myocardial lesion (fig. 1).