Miocardiopatía dilatada: aspectos genéticos, infecciosos, inflamatorios y del sistema inmune / Dilated cardiomyopathy: genetics, infectious, inflammatory and immune aspects

En la última década se ha producido un incremento sustancial en el conocimiento de las bases genéticas de las cardiomiopatías, en consideración a lo cual las Sociedades Americanas y Europea de Cardiología, han propuesto una nueva clasificación con el fin de incluir tales aspectos, Aunque se carece de datos precisos, aproximadamente el 30% de los pacientes con miocardiopatías referidos para pruebas genéticas presentan una variante genética patogénica. En la herencia de la miocardiopatía dilatada familiar, la modalidad predominante es la autosómica dominante, siendo mucho menos frecuentes las ligadas al cromosoma X, la herencia autosómica recesiva y la mitocondrial. A su vez, pruebas provenientes de ensayos clínicos y experimentales indican que la infección, la inflamación y el sistema inmunológico están de alguna manera interrelacionados en los mecanismos patogénicos implicados en la miocardiopatía dilatada, No hay duda que en un futuro próximo las mejoras en la secuenciación de genes y el mayor conocimiento de la patogenia influirán decididamente en el diagnóstico, evaluación y tratamiento de esta entidad.

In the last time, a substantial increase in the knowledge of the genetic basis of cardiomyopathy has occurred. Therefore in the last decade the American Heart Association, the American College of Cardiology and the European Society of Cardiology have proposed a new revision of the classification of cardiomyopathies in order to include the genetic basis on the etiology, Although precise data are lacking, approximately 30% of patients currently referred for clinical genetic testing will be found to have a pathogenic genetic variant. The predominant mode of inheritance for familial dilated cardiomyopathy is autosomal dominant, with X linked autosomal recessive and mitochondrial inheritance being less frequent. Evidence from experimental and clinical trials indicates that infection, inflammation and the immune system are in some way interrelated on the pathogenic mechanisms involved in the dilated cardiomyopathy, There is no doubt that in the future, improvements in sequencing genes and insight into pathogenesis will influence the diagnosis, evaluation and management of familial dilated cardiomyopathy.

Expression of a recombinant branched chain alpha-oxo acid dehydrogenase complex E2 (BCOADC-E2) in insect cells and its immunoreactivity to autoimmune sera

Preparation of a pure autoantigen by way of recombinant DNA technology has an important value in an accurate diagnosis or prognosis of an autoimmune disease. BCOADC-E2 subunit, a mitochondrial protein, has been known to be the autoantigen of primary biliary cirrhosis (PBC), a chronic autoimmune liver disease, as well as idiopathic dilated cardiomypathy (IDCM), a chronic autoimmune heart disease. Recombinant form of this molecule had been expressed in E. coli but with low yield and severe degradation. Furthermore, sera from IDCM patients failed to recognized BCOADC-E2 molecule produced in prokaryotic expression system. In this study, a recombinant bovine BCOADC-E2 fusion protein has been expressed in insect cells using baculovirus expression system and analyzed anti-BCOADC-E2 reactivity in sera from patients with PBC or with IDCM. Optimal production of the recombinant fusion protein has been achieved at 20 multiplicity of infection (MOI), and the protein was affinity-purified using metal-binding resins. The affinity-purified BCOADC-E2 protein was successfully recognized by sera from PBC patients, but not by sera from IDCM patients suggesting that the different auto-immune response against BCOADC-E2 is needed to be elucidated in terms of epitope recognition.

Immunohistochemical characterisation and quantitative evaluation of lymphomononuclear cells in dilated cardiomyopathy-an endomyocardial biopsy study.

Endomyocardial biopsies (EMB) from patients of dilated cardiomyopathy (DCM) and normal hearts were evaluated for infiltration by lymphomononuclear cells. Cryostat sections from cases of DCM were stained with antisera against leucocyte common antigen (LCA), Pan T lymphocytes and macrophages. Paraffin sections from patients of DCM and normal hearts were also stained with a panel of antisera against LCA, and macrophage markers namely, lysozyme, alpha-1-antitrypsin (AAT) and alpha-1-antichymotrypsin (ACT). The stained cells were quantitated and expressed as number of cells/mm2. Comparisons were made between the number of lymphomononuclear cells in hematoxylin and eosin stained sections and those stained by various markers. Light microscopic evaluation of paraffin sections of EMB in all cases of DCM showed mild to moderate hypertrophy of the myocardium in 20 and 10 patients respectively. Only mild focal myonecrosis was observed in 14 patients. These foci showed minimal infiltration by lymphomononuclear cells. In normal hearts, occasional small foci of lymphomononuclear cells were seen within the interstitium. The number of LCA positive cells in the frozen section from cases of DCM were more (7.03 +/- 3.15/mm2) than the number of cells in the corresponding paraffin sections (5.26 +/- 1.14/mm2), thus indicating that antigens are possibly better preserved in frozen sections. In normal hearts, the number of cells staining positively with LCA were almost identical (4.81 +/- 1.14/mm2) to those seen in paraffin sections of cases of DCM (5.26 +/- 1.61/mm2).(ABSTRACT TRUNCATED AT 250 WORDS)

Estudio de la inmunidad humoral en pacientes con miocardiopatía dilatada / Study of humoral immunity in patients presenting with dilated cardiomyopathy

Se estudió la respuesta inmune humoral en 42 pacientes con miocardiopatía dilatada y en 30 individuos sanos como grupo control. Al compparar los resultados de pacientes y controles, los niveles de inmunocomplejos circulantes determinados por la prueba desviación de Clq resultaron de las pruebas de inhibición de la precipitación de inmunocomplejos (p<0,001) y de la solubilización de inmunocomplejos (p<0,05). Los niveles de inmunoglobulinas séricas IgG e IgA se encontraron significativamente elevadas (p<0,001 en ambos casos). El estudio del sistema complemento reveló un aumento de los valores de la actividad total de la vía alternativa (p<0,001), así como de la actividad hemolítica del factor B (p<0,05) y disminución de los valores de C3 (p<0,05). Las alteraciones de la inmunidad humoral encontradas, sugieren la presencia de un proceso inflamatorio que pudiera estar desencadenado por un mecanismo autoinmune

Significance of pathological parameters of endomyocardial biopsy in clinical outcome of patients of dilated cardiomyopathy--II. Value of cardiac immune complexes and heart reactive antibodies.

We have evaluated the status of cardiac immune complexes and heart reactive antibodies in endomyocardial biopsies (EMB) and patients' sera from cases of dilated cardiomyopathy (DCM) using immunofluorescence. This was done with an aim to test whether this parameter can be of diagnostic and/or prognostic value in cases of DCM in its inflammatory and non inflammatory stages. Deposition of IgG was consistently observed in all cases of DCM regardless of the presence or absence of inflammation. Complement was detected in only a few while IgG and C3 together was seen to be deposited in only 4 cases. IgA and IgM were noted in an occasional case only. Heart reactive antibodies were seen in 13 of the 23 cases of DCM. Light microscopically, in 7 of the 23 biopsies mild focal lymphocytic myocarditis was detected. Presence of IgG in EMB and a low left ventricular ejection fraction (LVEF 35%) in almost all the cases, highlight the prognostic significance of IgG (in EMB) as an independent parameter. Based on this small study, it is difficult to attach significance to these observations as regards predicting the outcome of these patients. Nevertheless, the present study initiates evaluation of one of the parameters which is accessible and can be easily carried out in most routine laboratories for diagnosis, prognosis, and eventually monitoring of therapy in patients of DCM. Importance of immunofluorescence technique can be further strengthened by evaluating a larger number of cases with varying duration of symptoms and a follow up study of cases of DCM.

Immunopathologic studies in myocardial biopsies of patients with Chagas' disease and idiopathic cardiomyopathy

Foram estudadas biópsias de ventrículo direito de 30 pacientes, 15 com doença crônica de Chagas e 15 com miocardiopatia congestiva idiopática. Analisou-se também cinco fragmentos miocárdicos obtidos de pacientes chagásicos com menos de duas horas de óbito. Os autores tentaram estabelecer, por meio de técnica de imunofluorescência direta, a presença de imunoglobulina G, A, e M, fibrinogênio e C3. Somente uma das 30 biópsias exibiu reaçäo positiva para IgG que era de um paciente com miocardiopatia congestiva idiopática. Todos os fragmentos provenientes de pacientes chagásicos näo apresentaram qualquer fluorescência com nenhum dos conjugados