Overexpression of scavenger receptor and infiltration of macrophage in epicardial adipose tissue of patients with ischemic heart disease and diabetes.

BACKGROUND: Oxidized low-density lipoproteins and scavenger receptors (SRs) play an important role in the formation and development of atherosclerotic plaques. However, little is known about their presence in epicardial adipose tissue (EAT). The objective of the study was to evaluate the mRNA expression of different SRs in EAT of patients with ischemic heart disease (IHD), stratifying by diabetes status and its association with clinical and biochemical variables. METHODS: We analyzed the mRNA expression of SRs (LOX-1, MSR1, CXCL16, CD36 and CL-P1) and macrophage markers (CD68, CD11c and CD206) in EAT from 45 patients with IHD (23 with type 2 diabetes mellitus (T2DM) and 22 without T2DM) and 23 controls without IHD or T2DM. RESULTS: LOX-1, CL-P1, CD68 and CD11c mRNA expression were significantly higher in diabetic patients with IHD when compared with those without T2DM and control patients. MSR1, CXCL16, CD36 and CD206 showed no significant differences. In IHD patients, LOX-1 (OR 2.9; 95% CI 1.6-6.7; P = 0.019) and CD68 mRNA expression (OR 1.7; 95% CI 0.98-4.5; P = 0.049) were identified as independent risk factors associated with T2DM. Glucose and glycated hemoglobin were also shown to be risk factors. CONCLUSIONS: SRs mRNA expression is found in EAT. LOX-1 and CD68 and were higher in IHD patients with T2DM and were identified as a cardiovascular risk factor of T2DM. This study suggests the importance of EAT in coronary atherosclerosis among patients with T2DM.

Impact of dynamic physical exercise on high-risk definite arrhythmogenic right ventricular cardiomyopathy.

INTRODUCTION: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy characterized by ventricular arrhythmias and heart failure. The variable phenotype suggesting that determined environmental factors may have an influence. The aim of our study was to discover the impact of the dynamic physical activity on patients with high-risk definite ARVC/D. METHODS AND RESULTS: Collection of data on physical activity at the time of diagnosis was conducted at an in-person clinical interview. The intensity of the activity was classified in accordance with the mean frequency of weekly physical exercise sessions in the 10 years before diagnosis and into the following three groups of dynamic activity: high/competitive (>3 h/wk), moderate (1 to 3 h) and minimal/inactive (<1 h). Seventeen patients practiced high dynamic physical activities. The intensity of dynamic activity was classified into three groups: 8 of high intensity, 9 moderate, and 19 inactive. The first major arrhythmic event and occurrence of severe right ventricular dysfunction were earlier in the high-intensity exercise group, followed by the moderate intensity group and at a later age in the low-intensity/inactive group. CONCLUSIONS: Dynamic exercise could be directly associated with the severity of the phenotype in relation to the precocity of major ventricular arrhythmic events and right ventricular systolic dysfunction in patients with high-risk definite ARVC/D.

Expression of epicardial adipose tissue thermogenic genes in patients with reduced and preserved ejection fraction heart failure.

Epicardial adipose tissue has been proposed to participate in the pathogenesis of heart failure. The aim of our study was to assess the expression of thermogenic genes (Uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), and PR-domain-missing 16 (PRDM16) in epicardial adipose tissue in patients with heart failure, stablishing the difference according to left ventricular ejection fraction (reduced or preserved). Among the 75 patients in our study, 42.7% (n=32) had reduced left ventricular ejection fraction. UCP1, PGC1α and PRDM16 mRNA in EAT were significantly lower in patients with reduced left ventricular ejection fraction. Multiple regression analysis showed that age, male gender, body max index, presence of obesity, type-2-diabetes mellitus, hypertension and coronary artery disease and left ventricular ejection fraction were associated with the expression levels of UCP1, PGC1α and PRDM16 mRNA. Thermogenic genes expressions in epicardial adipose tissue (UCP1: OR 0.617, 95%CI 0.103-0.989, p=0.042; PGC1α: OR 0.416, 95%CI 0.171-0.912, p=0.031; PRDM16: OR 0.643, 95%CI 0.116-0.997, p=0.044) were showed as protective factors against the presence of heart failure with reduced left ventricular ejection fraction, and age (OR 1.643, 95%CI 1.001-3.143, p=0.026), presence of coronary artery disease (OR 6.743, 95%CI 1.932-15.301, p<0.001) and type-2-diabetes mellitus (OR 4.031, 95%CI 1.099-7.231, p<0.001) were associated as risk factors. The adequate expression of thermogenic genes has been shown as possible protective factors against heart failure with reduced ejection fraction, suggesting that a loss of functional epicardial adipose tissue brown-like features would participate in a deleterious manner on heart metabolism. Thermogenic genes could represent a future novel therapeutic target in heart failure.

Phenotype and progression among patients with dilated cardiomyopathy and RBM20 mutations.

BACKGROUND: Over 70 genes that encode different cell components have been involved in the aetiology of dilated cardiomyopathy. Genotype-phenotype interactions are an unsolved problem, and to a large extent the effects of mutations in the expression mechanisms involved in the disease remain unknown, although associations are increasingly being established which have clinical and prognostic implications. METHODS AND RESULTS: The objective of our work was to describe our population that has cardiomyopathy associated with mutations in the gene RBM20, and study the genotype-phenotype relationship. We studied 8 cases undergoing follow-up at our Unit, and collected data for demographic, clinical and diagnostic testing variables. The mean age on diagnosis was 55 years [52-59], with a median follow-up of 31.5 months [26.0-67.3]. It is worth noting that 62.5% of the patients in our group had a history of cardiomyopathy in first degree relatives, and 37.5% of them had a family history of sudden death. One of the genetic variations of the sample was shared by three subjects who had no apparent family relationship with each other, and this variation had not been described in controls. It is also interesting that arrhythmic events were found in 37.5% of the sample, and 50% of patients had an indication for implantable cardiac defibrillator. CONCLUSION: This is the first analysis of patients with RBM20 mutations conducted in our country, and it indicates a profile with prominent arrhythmogenesis, a high penetrance of familial cardiomyopathy, and sudden death.

Usefulness of Genetic Study by Next-generation Sequencing in High-risk Arrhythmogenic Cardiomyopathy.

INTRODUCTION AND OBJECTIVES: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of predominantly right ventricular myocardium. This cardiomyopathy is a frequent cause of sudden cardiac death in young people and athletes. The aim of our study was to determine the incidence of pathological or likely pathological desmosomal mutations in patients with high-risk definite ARVC. METHODS: This was an observational, retrospective cohort study, which included 36 patients diagnosed with high-risk ARVC in our hospital between January 1998 and January 2015. Genetic analysis was performed using next-generation sequencing. RESULTS: Most patients were male (28 patients, 78%) with a mean age at diagnosis of 45 ± 18 years. A pathogenic or probably pathogenic desmosomal mutation was detected in 26 of the 35 index cases (74%): 5 nonsense, 14 frameshift, 1 splice, and 6 missense. Novel mutations were found in 15 patients (71%). The presence or absence of desmosomal mutations causing the disease and the type of mutation were not associated with specific electrocardiographic, clinical, arrhythmic, anatomic, or prognostic characteristics. CONCLUSIONS: The incidence of pathological or likely pathological desmosomal mutations in ARVC is very high, with most mutations causing truncation. The presence of desmosomal mutations was not associated with prognosis.

Incidence and prognosis implications of long term left ventricular reverse remodeling in patients with dilated cardiomyopathy.

BACKGROUND: Left ventricular reverse remodeling (LVRR) in dilated cardiomyopathy is poorly known within the context of current therapeutic approach. Our goal is to describe the present incidence of LVRR, the factors able to predict it and the long term prognosis of these patients. METHODS AND RESULTS: We performed a retrospective analysis of a cohort or 387 consecutive outpatients. Mean follow-up was 50.4 ± 28.4 months. Sustained LVRR occurred in 57.6% of patients. The number of coronary arteries with severe stenosis (HR 0.69, 95% CI 0.55-0.86; p=0.001), New York Heart Association Functional Class (NYHA FC) (HR 0.39, 95% CI 0.27-0.54; p<0.001) as well as the severity of mitral regurgitation (MR) at the end of follow-up (HR 0.42, 95% CI 0.30-0.58; p<0.001) and the time until first event (HR 1.02, 95% CI 1.01-1.03; p<0.001) were independent predictors of left ventricular ejection fraction improvement. LVRR was tightly related to prognosis due to the fact that both improvement in cardiac function achieving normal or slightly impaired LVEF (HR 0.31, 95% CI 0.17-0.56; p<0.001) and shorter time to achieve LVRR (HR 0.99, 95% CI 0.98-0.99; p=0.017) formed part of the best model for predicting events in DCM. CONCLUSION: More than half of the patients showed sustained LVRR associated with a significantly better prognosis. Fewer numbers of coronary arteries with severe stenosis, milder NYHA FC and the absence of significant MR at the end of follow-up as well as longer event free period formed a simple model to prognosticate LVRR. LVRR and the time to achieve it were strongly related to long term prognosis in patients with DCM.

[Systolic ventricular dysfunction, a new marker of coronary artery disease in patients with aortic stenosis without previous myocardial infarction]. / Disfunción ventricular sistólica, un nuevo marcador de enfermedad coronaria en pacientes con estenosis aórtica sin infarto de miocardio previo.

Identification of clinical factors associated with coronary artery disease could obviate the need for coronary angiography in selected patients with severe aortic stenosis. We studied 315 patients (68 [8] years) with severe aortic stenosis without previous infarction who underwent coronary angiography. In the univariate analysis, age (P = .001), dyslipidemia (P = .003), angina (P = .018), aortic gradient (P = .001) and reduced ejection fraction (P = .006) were predictors of coronary artery disease. After multivariate analysis, age (OR = 1.079, P = .01), ejection fraction < 40% (OR = 2.685, P = .02), angina (OR = 2.518, P = .04) and dyslipidemia (OR = 2.34, P = .008) were the factors independently associated with coronary artery disease. Left ventricular dysfunction correlated independently with the presence of coronary artery disease.

[Dynamic left ventricular outflow tract obstruction induced by exercise]. / Obstrucción dinámica intraventricular izquierda inducida por esfuerzo.

INTRODUCTION AND OBJECTIVES: Dynamic left intraventricular outflow tract obstruction occurs occasionally in patients without hypertrophic cardiomyopathy. We hypothesized that dynamic intraventricular obstruction might occur during effort in patients with angina or dyspnea without evident disease. The objective of this prospective study was to investigate: a) whether it appears with effort; b) its incidence, magnitude and determining factors, and c) its clinical course. PATIENTS AND METHOD: We performed baseline and stress Doppler echocardiography in 211 patients with angina, dyspnea or both with exercise. Patients with previous myocardial infarction, valvular heart disease, ventricular dysfunction or ventricular hypertrophy without hypertension were excluded. Dynamic intraventricular obstruction was defined as intracavitary flow velocity > or =2.5 m/s. RESULTS: 134 patients (59 women) were included: mean age was 58 (9) years; history of hypertension was present in 69.7%, dyslipidemia in 35.8% and diabetes in 24.6%. Dynamic intraventricular obstruction appeared in 18 patients (13.4%), with gradients ranging between 25 and 53 mmHg (mean 32.19 [6.6]). Demographic variables, cardiovascular risk factors and exercise performed were similar in group A (with obstruction) and group B (without obstruction). No patient in group A had evidence of ischemia. Five patients in this group had symptoms during exercise; the gradients were greater in these patients (42.65 [10.5] vs 28.15 [2.37] mmHg; P<.0001) than in the remaining group A patients. Left ventricular outflow tract size was found to be the only independent predictive factor in the multivariate analysis. After 369.9 (133.5) days of follow-up, no cardiac events were recorded. CONCLUSIONS: Our study suggests that some patients with angina or dyspnea without evidence of ischemia may develop dynamic left ventricular outflow tract obstruction induced by effort.

Rentabilidad del estudio genético mediante técnicas de next-generation sequencing masiva de pacientes con miocardiopatía arritmogénica de alto riesgo / Usefulness of genetic study by next-generation sequencing in high-risk arrhythmogenic cardiomyopathy

Introducción y objetivos: La miocardiopatía arritmogénica del ventrículo derecho (MCAVD) es una cardiopatía hereditaria definida por la sustitución progresiva de miocardio ventricular derecho por tejido fibroadiposo. Es causa frecuente de la muerte súbita de jóvenes atletas. El objetivo del presente estudio es conocer la incidencia de variantes desmosómicas patogénicas o probablemente patogénicas en pacientes con MCAVD definitiva de alto riesgo. Métodos: El estudio de cohortes retrospectivo observacional incluyó a 36 pacientes diagnosticados de MCAVD definitiva de alto riesgo en nuestro hospital entre enero de 1998 y enero de 2015. El análisis genético se realizó con next-generation sequencing. Resultados: La mayoría eran varones (28 pacientes, 78%) con una media de edad al diagnóstico de 45 ± 18 años. Se detectó al menos 1 variante desmosómica patogénica o probablemente patogénica en 26 de los 35 casos índice (74%): 5 nonsense, 14 frameshift, 1 splice y 6 missense. En 15 pacientes (71%) se encontraron mutaciones nuevas. La presencia o la ausencia de mutaciones desmosómicas o la naturaleza de estas no se asociaron con características electrocardiográficas, clínicas, arrítmicas, anatómicas o pronósticas específicas. Conclusiones: La incidencia de variantes desmosómicas patogénicas o probablemente patogénicas en MCAVD definitiva de alto riesgo fue muy alta, con mayoría de mutaciones que causan truncamiento. La presencia de mutaciones desmosómicas no se asoció con el pronóstico

Introduction and objectives: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of predominantly right ventricular myocardium. This cardiomyopathy is a frequent cause of sudden cardiac death in young people and athletes. The aim of our study was to determine the incidence of pathological or likely pathological desmosomal mutations in patients with high-risk definite ARVC. Methods: This was an observational, retrospective cohort study, which included 36 patients diagnosed with high-risk ARVC in our hospital between January 1998 and January 2015. Genetic analysis was performed using next-generation sequencing. Results: Most patients were male (28 patients, 78%) with a mean age at diagnosis of 45 ± 18 years. A pathogenic or probably pathogenic desmosomal mutation was detected in 26 of the 35 index cases (74%): 5 nonsense, 14 frameshift, 1 splice, and 6 missense. Novel mutations were found in 15 patients (71%). The presence or absence of desmosomal mutations causing the disease and the type of mutation were not associated with specific electrocardiographic, clinical, arrhythmic, anatomic, or prognostic characteristics. Conclusions: The incidence of pathological or likely pathological desmosomal mutations in ARVC is very high, with most mutations causing truncation. The presence of desmosomal mutations was not associated with prognosis

Disfunción ventricular sistólica, un nuevo marcador de enfermedad coronaria en pacientes con estenosis aórtica sin infarto de miocardio previo / Systolic ventricular dysfunction, a new marker of coronary artery disease in patients with aortic stenosis without previous myocardial infarction

La determinación de factores clínicos predictivos de la presencia de enfermedad coronaria podría obviar la necesidad de realizar una coronariografía en pacientes seleccionados con estenosis aórtica severa. Se estudió a315 pacientes (68 ± 8 años) sin infarto previo con estenosis aórtica severa a los que se realizó coronariografía. En el análisis univariable, resultaron significativas la edad (p = 0,001), la dislipemia (p = 0,003), la angina (p =0,018), el gradiente aórtico (p = 0,001) y la fracción deeyección (FE) reducida (p = 0,006). En el análisis multivariable las variables asociadas de forma independiente ala lesión coronaria fueron la edad (odds ratio [OR] =1,079, p = 0,01), la FE < 40% (OR = 2,685, p = 0,02), la angina (OR = 2,518, p = 0,04) y la dislipemia (OR = 2,34,p = 0,008).La disfunción ventricular se correlaciona de forma independiente con la presencia de lesiones coronarias

Identification of clinical factors associated with coronaryartery disease could obviate the need for coronary angiography in selected patients with severe aortic stenosis.We studied 315 patients (68 [8] years) with severe aortic stenosis without previous infarction who underwent coronary angiography. In the univariate analysis, age(P=.001), dyslipidemia (P=.003), angina (P=.018), aortic gradient (P=.001) and reduced ejection fraction (P=.006)were predictors of coronary artery disease. After multivariate analysis, age (OR = 1.079, P=.01), ejection fraction< 40% (OR = 2.685, P=.02), angina (OR = 2.518, P=.04) and dyslipidemia (OR = 2.34, P=.008) were the factors independently associated with coronary artery disease. Left ventricular dysfunction correlated independently with the presence of coronary artery disease

Obstrucción dinámica intraventricular izquierda inducida por esfuerzo / Dynamic Left Ventricular Outflow Tract Obstruction Induced by Exercise

Introducción y objetivos. La obstrucción dinámica intraventricular izquierda puede aparecer ocasionalmente en pacientes sin miocardiopatía hipertrófica. Planteamos si podría aparecer inducida por esfuerzo en pacientes con angina o disnea de esfuerzo sin causa aparente. El objetivo de este estudio prospectivo es conocer: a) si aparece con esfuerzo; b) su incidencia, magnitud y factores determinantes, y c) evolución de los pacientes que la presentan. Pacientes y método. Realizamos ecocardiograma Doppler basal y postesfuerzo en 211 pacientes con angina o disnea de esfuerzo. Excluimos a los que tenían infarto previo, valvulopatía, disfunción ventricular o hipertrofia ventricular sin hipertensión. Definimos obstrucción dinámica intraventricular como flujo intraventricular con velocidad ≥ 2,5 m/s. Resultados. Se incluyó a 134 pacientes (59 mujeres), con una edad de 58 ± 9 años; el 69,7% tenía antecedentes de hipertensión, el 35%, dislipemia y el 24,6%, diabetes. Apareció obstrucción intraventricular en 18 (13,4%) pacientes, con un gradiente entre 25 y 53 mmHg (media, 32,19 ± 6,6). Las variables demográficas, los factores de riesgo y el ejercicio realizado fueron similares en el grupo A (con obstrucción) y B (sin obstrucción). En el grupo A, ningún paciente tuvo evidencia de isquemia y los 5 que presentaron síntomas durante el esfuerzo tuvieron mayores gradientes (42,65 ± 10,5 frente a 28,15 ± 2,37 mmHg; p < 0,0001) que el resto del grupo A. El análisis multivariante identificó el diámetro del tracto de salida como único factor predictor independiente. Tras un seguimiento de 369,9 ± 133,5 días, no se registraron eventos. Conclusiones. Nuestros datos sugieren que algunos pacientes con angina o disnea de esfuerzo sin evidencia de isquemia pueden tener obstrucción dinámica ventricular izquierda inducida por esfuerzo (AU)

Introduction and objectives. Dynamic left intraventricular outflow tract obstruction occurs occasionally in patients without hypertrophic cardiomyopathy. We hypothesized that dynamic intraventricular obstruction might occur during effort in patients with angina or dyspnea without evident disease. The objective of this prospective study was to investigate: a) whether it appears with effort; b) its incidence, magnitude and determining factors, and c) its clinical course. Patients and method. We performed baseline and stress Doppler echocardiography in 211 patients with angina, dyspnea or both with exercise. Patients with previous myocardial infarction, valvular heart disease, ventricular dysfunction or ventricular hypertrophy without hypertension were excluded. Dynamic intraventricular obstruction was defined as intracavitary flow velocity ≥2.5 m/s. Results. 134 patients (59 women) were included: mean age was 58 (9) years; history of hypertension was present in 69.7%, dyslipidemia in 35.8% and diabetes in 24.6%. Dynamic intraventricular obstruction appeared in 18 patients (13.4%), with gradients ranging between 25 and 53 mmHg (mean 32.19 [6.6]). Demographic variables, cardiovascular risk factors and exercise performed were similar in group A (with obstruction) and group B (without obstruction). No patient in group A had evidence of ischemia. Five patients in this group had symptoms during exercise; the gradients were greater in these patients (42.65 [10.5] vs 28.15 [2.37] mmHg; P<.0001) than in the remaining group A patients. Left ventricular outflow tract size was found to be the only independent predictive factor in the multivariate analysis. After 369.9 (133.5) days of follow-up, no cardiac events were recorded. Conclusions. Our study suggests that some patients with angina or dyspnea without evidence of ischemia may develop dynamic left ventricular outflow tract obstruction induced by effort (AU)