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.

Detection and comparison of microRNA expression in the serum of Doberman Pinschers with dilated cardiomyopathy and healthy controls.

BACKGROUND: Dilated cardiomyopathy (DCM) is the most common heart disease in Doberman Pinschers. MicroRNAs (miRNAs) are short non-coding RNAs playing important roles in gene regulation. Different miRNA expression patterns have been described for DCM in humans and might represent potential diagnostic markers. There are no studies investigating miRNA expression profiles in canine DCM. The aims of this study were to screen the miRNA expression profile of canine serum using miRNA microarray and to compare expression patterns of a group of Doberman Pinschers with DCM and healthy controls. RESULTS: Eight Doberman Pinschers were examined by echocardiography and 24-hour-ECG and classified as healthy (n=4) or suffering from DCM (n=4). Total RNA was extracted from serum and hybridized on a custom-designed 8x60k miRNA microarray (Agilent) containing probes for 1368 individual miRNAs. Although total RNA concentrations were very low in serum samples, 404 different miRNAs were detectable with sufficient signal intensity on miRNA microarray. 22 miRNAs were differentially expressed in the two groups (p<0.05 and fold change (FC)>1.5), but did not reach statistical significance after multiple testing correction (false discovery rate adjusted p>0.05). Five miRNAs were selected for further analysis using quantitative Real-Time RT-PCR (qPCR) assays. No significant differences were found using specific miRNA qPCR assays (p>0.05). CONCLUSIONS: Numerous miRNAs can be detected in canine serum. Between healthy and DCM dogs, miRNA expression changes could be detected, but the results did not reach statistical significance most probably due to the small group size. miRNAs are potential new circulating biomarkers in veterinary medicine and should be investigated in larger patient groups and additional canine diseases.

Miocarditis y miocardiopatía dilatada por Trypanosoma cruzi: reporte de un caso / Myocarditis and dilated myocardiopathy by Trypanosoma cruzi: case report

The agent of Chagas disease, Trypanosoma cruzi, is one of the major causes of myocarditis and dilated myocardiopathy in America. In Costa Rica, the latest studies revealed that the improvement of the general live conditions, has decreased the Chagas disease incidence in this country and its deadly complications. We described the clinical history and the autopsy findings of an infrequent case of death by this disease in Costa Rica, represented by myocarditis and dilated myocardiopathy manifestations caused by T. cruzi, where the diagnosis was made post-mortem.

El Trypanosoma cruzi, agente causal de la Enfermedad de Chagas, constituye una de las principales causas de miocarditis y miocardiopatía dilatada en el continente americano. En Costa Rica, las últimas encuestas indican que las mejores condiciones de vida actuales han disminuido la incidencia de esta enfermedad y por consiguiente sus complicaciones; sin embargo, en el presente artículo se describió el cuadro clínico y los hallazgos de autopsia, de uno de los pocos casos de muerte por esta parasitosis en Costa Rica; se trata de un caso de miocarditis y miocardiopatía dilatada causada por T. cruzi, cuyo diagnóstico fue hecho post mortem.

Substance P is associated with heart enlargement and apoptosis in murine dilated cardiomyopathy induced by Taenia crassiceps infection.

Dilated cardiomyopathy (degeneration of heart muscle and heart enlargement) is an important cause of heart failure among young adults. Dilated cardiomyopathy may be a complication during or after various viral, bacterial, or parasitic diseases. Substance P (SP) is a neurotransmitter that is involved in the pathogenesis of various diseases. To determine whether SP is associated with cardiac changes in murine cysticercosis, we compared heart-weight to body-weight ratio, cardiac pathology, cardiomyocyte size, and cardiac-apoptosis (TUNEL assay) in hearts from Taenia crassiceps-infected (wild-type vs. SP-knockout) mice. We noted that, as compared with control uninfected wild-type mice, elevated protein levels of SP and its receptor as studied by ELISA or immunohistochemistry, respectively, were elevated in the hearts of parasite-infected wild-type mice. The heart-weight to body-weight ratios were significantly higher in the parasite-infected wild-type mice versus those of the infected SP-knockout mice. Furthermore, wild-type infected mice developed dilated cardiomyopathy with increased chamber size of both ventricles, decreased ventricular wall thickness, compensatory cardiomyocyte hypertrophy, and increased cardiac apoptosis. This cardiac pathology did not develop in mice lacking SP activity (i.e., in infected SP knockout mice) or in uninfected mice. These data indicate that SP is associated with cardiac changes in an animal model of parasitic dilated cardiomyopathy.

[Chagasic myocardiopathy: an infectious etiology of congestive heart failure]. / Miocardiopatía chagásica: una causa de insuficiencia cardiaca de origen infeccioso.

We present a case report of a Latin-American patient with dilated cardiomyopathy due to chronic Chagas disease satisfactorily treated with usual cardiologic support. We report a new aetiology of heart failure which is uncommon in our country but could rise due to immigration from endemic countries.

Evaluation of cardiac lesions and risk factors associated with myocarditis and dilated cardiomyopathy in southern sea otters (Enhydra lutris nereis).

OBJECTIVE: To describe cardiac lesions and identify risk factors associated with myocarditis and dilated cardiomyopathy (DCM) in beach-cast southern sea otters. ANIMALS: Free-ranging southern sea otters. PROCEDURE: Sea otters were necropsied at the Marine Wildlife Veterinary Care and Research Center from 1998 through 2001. Microscopic and gross necropsy findings were used to classify sea otters as myocarditis or DCM case otters or control otters. Univariate, multivariate, and spatial analytical techniques were used to evaluate associations among myocarditis; DCM; common sea otter pathogens; and potential infectious, toxic, and nutritional causes. RESULTS: Clusters of sea otters with myocarditis and DCM were identified in the southern aspect of the sea otter range from May to November 2000. Risk factors for myocarditis included age, good body condition, and exposure to domoic acid and Sarcocystis neurona. Myocarditis associated with domoic acid occurred predominantly in the southern part of the range, whereas myocarditis associated with S. neurona occurred in the northern part of the range. Age and suspected previous exposure to domoic acid were identified as major risk factors for DCM. A sample of otters with DCM had significantly lower concentrations of myocardial L-carnitine than control and myocarditis case otters. CONCLUSIONS AND CLINICAL RELEVANCE: Cardiac disease is an important cause of death in southern sea otters. Domoic acid toxicosis and infection with S. neurona are likely to be 2 important causes of myocarditis in sea otters. Domoic acid-induced myocarditis appears to progress to DCM, and depletion of myocardial L-carnitine may play a key role in this pathogenesis.

[Specific dilated myocardiopathy. Chronic chagasic cardiopathy at the National Institute of Cardiology Ignacio Chávez]. / Miocardiopatía dilatada específica. La cardiopatía chagásica crónica en el Instituto Nacional de Cardiología Ignacio Chávez.

Cardiomyopathies are a heterogenous group of heart ailments. Some of them are primary myocardial diseases and are classified as dilated, hypertrophic, restrictive and arryhithmogenic. Dilated cardiomyopathies (DCs) are the most common. Sometimes it is possible to identify an etiologic agent, in that case we talk about a specific dilated cardiomyopathy. Here in, we review one of these specific DCs, the so called Chronic Chagasic Cardiopathy (CCC) from the point of view of our personal experience at the Instituto Nacional de Cardiología "Ignacio Chávez". Chagas' disease is present in Mexico, therefore CCC is also present. We estimate that 5,000 people, suffer CCC with severe symptoms. In Mexico, Chagas' disease occurs below the Tropic of Cancer and between 2,000-2,500 m above sea level, in this area there is a real risk for vectorial infection, mainly in rural villages. Clinical diagnosis should be supported by epidemiological and seroepidemiological confirmatory data. There is not appropriate therapy yet for this condition.

Predictors of unfavourable prognosis in chronic Chagas' disease.

The aim of this study was to detect clinical predictors of left ventricular dysfunction, left ventricular dilatation and apical aneurysm on echocardiography, all known as independent predictors of lethal outcome for patients with chronic Chagas' disease. Seventy-four patients with a positive complement-fixation test for Chagas' disease participated; 44 (59%) had left ventricular dysfunction, 41 (55%) left ventricular dilatation and 15 (20%) apical aneurysm. A stepwise logistic regression analysis showed that systolic blood pressure (P < 0.001) and male sex (P < 0.001) were independent predictors of left ventricular dilatation on echocardiography. A receiver-operating characteristic curve provided a systolic blood pressure of 120 mmHg with a sensitivity of 70% and a specificity of 63% to predict left ventricular dilatation. The combination of male sex and systolic blood pressure of 120 mmHg had a sensitivity of 56% and a specificity of 91% to predict left ventricular dilatation. In a separate stepwise logistic regression analysis, left ventricular systolic dysfunction was independently predicted by systolic blood pressure (P = 0.006) and New York Heart Association functional class (P = 0.01). Receiver-operating curves provided a blood pressure of 120 mmHg with a sensitivity of 72% and a specificity of 59% to predict left ventricular dysfunction, whereas a New York Heart Association functional score of 2 predicted left ventricular systolic dysfunction with a sensitivity of 78% and a specificity of 50%. The combination of New York Heart Association functional class and a systolic blood pressure of 120 mmHg predicted left ventricular dysfunction with a sensitivity of 59% and a specificity of 77%. The apical aneurysm was independently predicted by myocardial necrosis on the resting ECG, but only with a sensitivity of 20%. Hence, echocardiographic markers of cardiac mortality and sudden cardiac death in Chagas' disease can be independently predicted by clinical examination. This may be useful for screening high-risk chagasic patients.

Immunopathological mechanisms underlying the time-course of Trichinella spiralis cardiomyopathy in rats.

The present study shows that isolated, perfused hearts from rats orally infected with Trichinella spiralis have a reduced left ventricular developed pressure (LVDP), heart rate (HR) and coronary flow (CF). This reduction is considerably enhanced by a single bolus (100 pM) of PAF (platelet activating factor, an eosinophil activator), especially at 21 days post-infection (d.p.i.), which is the time of the maximum increase in blood and tissue eosinophilia. Helminthic DNA analysis shows that, from 21 d.p.i. onwards, the morphological and functional changes in the myocardium cannot be ascribed to the parasite's presence, whereas its antigens and the attendant immunopathological reactions might have a role in the induction of myocardial damage and dysfunction. Some perivascular inflammatory cells (eosinophils and mast cells) appear to undergo degranulation. All these data suggest a complex sequence of events, from acute myocarditis (21 d.p.i.) which may lead in time (48 d.p.i. onwards) to a dilating cardiomyopathy.

Sera from chronic chagasic patients with complex cardiac arrhythmias depress electrogenesis and conduction in isolated rabbit hearts.

BACKGROUND: Immune dysfunction has long been proposed as a mechanism for the etiopathogenesis of the chronic phase of Chagas' disease. Antibodies of chagasic patients have been shown to interfere with electric and mechanical activity of embryonic myocardial cells in culture. Here, we demonstrate that antibodies derived from a group of chronic chagasic patients are able to induce disturbances in the electrogenesis and conduction in isolated adult rabbit hearts. METHODS AND RESULTS: Sera from chronic chagasic patients with complex cardiac arrhythmias (ChA+) decreased heart rate (from 131+/-26 to 98+/-37 bpm [mean+/-SD]; n=6; P<.05) in isolated rabbit hearts when perfused at a dilution of 1:100 (vol:vol) by the Langendorff method. Sera from another experimental group of four chronic chagasic patients without complex arrhythmias (ChA-) and two control groups composed of five Wolff-Parkinson-White (WPW) syndrome patients and five orthopedic surgery patients did not affect heart rate when tested under similar conditions. In addition, sera from five of six ChA+ patients and from one WPW patient induced AV conduction blockade. Effects of the sera from ChA+ patients are due to their IgG fractions. Both serum and IgG effects are blocked by atropine (10 micromol/L). CONCLUSIONS: Antibodies of ChA+ patients decrease heart rate and induce AV conduction block in isolated adult rabbit hearts through activation of muscarinic receptors.

Chronic chagasic cardiopathy with parasitemic state (preliminary report).

Seven patients with diagnosis of dilated myocardiopathy, who fulfilled epidemiological, clinical, and serological criteria for chronic American Trypanosomosis, were submitted to hemoculture. Parasites were isolated in two patients (29%) confirming diagnosis and indicating an infection. Antibody titers did not show any relationship with the presence or absence of parasitemia nor were clinical differences noticed. Isolated Trypanosoma cruzi parasites belonged to biodeme III.

Infections and dilated cardiomyopathy in Nigeria.

The relationship of infection to dilated cardiomyopathy is reviewed on the basis of 200 patients seen at University College Hospital, Ibadan. Evidence of infection with Toxoplasma and Coxsackie B viruses is presented. Clinically detectable myocarditis is rare in children, and the preponderance of dilated cardiomyopathy is in patients above the age of 30 years, possibly because there is a long latent period between the initial infection and the development of frank cardiomyopathy. This paper concluded that infections are probably the most important cause of dilated cardiomyopathy in Nigeria.