EpCAM y obstrucción microvascular en pacientes con un IAMCEST: estudio con resonancia magnética cardiaca / EpCAM and microvascular obstruction in patients with STEMI: a cardiac magnetic resonance study

Introducción y objetivos: La obstrucción microvascular (OMV) se asocia negativamente con la estructura cardiaca y el pronóstico de los pacientes tras un infarto agudo de miocardio con elevación del segmento ST (IAMCEST). El factor epithelial cell adhesion molecule (EpCAM), implicado en la cohesión de las células epiteliales, está poco estudiado en el contexto de la OMV. Por ello, el objetivo de este estudio es evaluar en una cohorte de pacientes con IAMCEST la asociación entre la concentración de EpCAM circulante con la extensión de la OMV, determinada por resonancia magnética cardiaca (RMC), y la función sistólica en fases crónicas. Métodos: Se incluyó prospectivamente a 106 pacientes con un primer IAMCEST tratados con angioplastia primaria percutánea. La concentración sérica de EpCAM se determinó 24h tras la reperfusión coronaria. Se estudió a todos los pacientes mediante RMC a la semana y a los 6 meses del IAMCEST. Se evaluó la correlación entre los valores de EpCAM circulante con la OMV, los índices de función sistólica y la fracción de eyección del ventrículo izquierdo. Resultados: La media de edad de la cohorte era 59±13 años y el 76% eran varones. Se dicotomizó a los pacientes según la mediana de EpCAM (4,48 pg/ml). Se observó que los pacientes que tenían valores más bajos de EpCAM presentaban una mayor extensión de la OMV (p=0,021) y un mayor tamaño de infarto (p=0,019) en los estudios de RMC realizados 1 semana después del evento cardiovascular. Respecto a las variables de presentación, la concentración de EpCAM se asoció significativamente con la presencia de OMV en análisis de regresión logística binaria univariable (OR=0,58; IC95%, 0,38-0,88; p=0,011) y multivariable (OR=0,55; IC95%, 0,35-0,87; p=0,010). A pesar de que la OMV tiende a resolverse espontáneamente en fases crónicas, unos valores más bajos de EpCAM se correlacionaron con una peor función sistólica (AU)

Introduction and objectives: Microvascular obstruction (MVO) is negatively associated with cardiac structure and worse prognosis after ST-segment elevation myocardial infarction (STEMI). Epithelial cell adhesion molecule (EpCAM), involved in epithelium adhesion, is an understudied area in the MVO setting. We aimed to determine whether EpCAM is associated with the appearance of cardiac magnetic resonance (CMR)-derived MVO and long-term systolic function in reperfused STEMI. Methods: We prospectively included 106 patients with a first STEMI treated with percutaneous coronary intervention, quantifying serum levels of EpCAM 24hours postreperfusion. All patients underwent CMR imaging 1 week and 6 months post-STEMI. The independent correlation of EpCAM with MVO, systolic volume indices, and left ventricular ejection fraction was evaluated. Results: The mean age of the sample was 59±13 years and 76% were male. Patients were dichotomized according to median EpCAM (4.48 pg/mL). At 1-week CMR, lower EpCAM was related to extensive MVO (P=.021) and larger infarct size (P=.019). At presentation, EpCAM values were significantly associated with the presence of MVO in univariate (OR, 0.58; 95%CI, 0.38-0.88; P=.011) and multivariate logistic regression models (OR, 0.55; 95%CI, 0.35-0.87; P=.010). Although MVO tends to resolve at chronic phases, decreased EpCAM was associated with worse systolic function: reduced left ventricular ejection fraction (P=.009) and higher left ventricular end-systolic volume (P=.043). Conclusions: EpCAM is associated with the occurrence of CMR-derived MVO at acute phases and long-term adverse ventricular remodeling post-STEMI

Punto de corte óptimo del antígeno carbohidrato 125 para la identificación de pacientes con bajo riesgo tras un ingreso por insuficiencia cardiaca aguda / Optimal carbohydrate antigen 125 cutpoint for identifying low-risk patients after admission for acute heart failure

Introducción y objetivos: El antígeno carbohidrato 125 (CA125) se ha mostrado útil para la estratificación del riesgo de los pacientes ingresados por insuficiencia cardiaca aguda (ICA). Se intenta determinar un punto de corte para identificar a los pacientes con bajo riesgo de muerte y muerte/reingreso por insuficiencia cardiaca 1 mes tras el ingreso por ICA. Métodos: La cohorte de derivación incluyó a 3.231 pacientes con ICA consecutivos. Se identificaron valores de corte de CA125 con un valor predictivo negativo (VPN) del 90% y una sensibilidad de hasta el 85%. La idoneidad de estos puntos de corte y el riesgo de muerte/reingreso al mes se evaluaron mediante el método de Royston-Parmar. Se seleccionó el mejor punto de corte y se validó en una cohorte del BIOSTAT-CHF (n=1.583). Resultados: En la cohorte de derivación, la mediana [intervalo intercuartílico] de CA125 fue 57 [25,3-157] U/ml. El punto de corte óptimo fue <23 U/ml (el 21,5% de los pacientes), con VPN de muerte y del objetivo compuesto del 99,3 y el 94,1% respectivamente. En los análisis multivariables, el CA125 <23 U/ml se asoció con un menores riesgos de muerte (HR=0,20; IC95%, 0,08-0,50; p <0,001) y del objetivo combinado (HR=0,63; IC95%, 950,45-0,90; p=0,009). Su capacidad para discriminar a los pacientes con riesgo bajo a 1 mes se confirmó en la cohorte de validación (VPN de muerte y del objetivo compuesto, el 98,6 y el 96,6%). La capacidad predictiva seguía siendo significativa a los 6 meses de seguimiento. Conclusiones: En pacientes ingresados por ICA, el CA125 <23 U/ml identificó un subgrupo de pacientes con bajo riesgo de eventos clínicos adversos a corto plazo que pueden no requerir un seguimiento estrecho (AU)

Introduction and objectives: Carbohydrate antigen 125 (CA125) has been shown to be useful for risk stratification in patients admitted with acute heart failure (AHF). We sought to determine a CA125 cutpoint for identifying patients at low risk of 1-month death or the composite of death/HF readmission following admission for AHF. Methods: The derivation cohort included 3231 consecutive patients with AHF. CA125 cutoff values with 90% negative predictive value (NPV) and sensitivity up to 85% were identified. The adequacy of these cutpoints and the risk of 1-month death/HF readmission was then tested using the Royston-Parmar method. The best cutpoint was selected and externally validated in a cohort of patients hospitalized from BIOSTAT-CHF (n=1583). Results: In the derivation cohort, the median [IQR] CA125 was 57 [25.3-157] U/mL. The optimal cutoff value was <23 U/mL (21.5% of patients), with NPVs of 99.3% and 94.1% for death and the composite endpoint, respectively. On multivariate survival analyses, CA125 <23 U/mL was independently associated with a lower risk of death (HR, 0.20; 95%CI, 0.08-0.50; P <.001), and the combined endpoint (HR, 0.63; 95%CI, 950.45-0.90; P=.009). The ability of this cutpoint to discriminate patients at a low 1-month risk was confirmed in the validation cohort (NPVs of 98.6% and 96.6% for death and the composite endpoint). The predicted ability of this cutoff remained significant at 6 months of follow-up. Conclusions: In patients admitted with AHF, CA125 <23 U/mL identified a subgroup at low risk of short-term adverse events, a population that may not require intense postdischarge monitoring (AU)

Differences in the Interleukin-1ß/Soluble ST2 Interplay Between Acute and Chronic Heart Failure.

Recently, novel findings about the interleukin 1ß (IL-1 ß) axis in acute decompensated heart failure (ADHF) have been published. There is a positive correlation between IL-1 ß and interleukin-1 receptor like 1 (sST2) in ADHF patients. Is there also a correlation between the values of IL-1 ß and sST2 in chronic heart failure patients?

Conformational and thermal characterization of left ventricle remodeling post-myocardial infarction.

Adverse cardiac remodeling after myocardial infarction (MI) causes impaired ventricular function and heart failure. Histopathological characterization is commonly used to detect the location, size and shape of MI sites. However, the information about chemical composition, physical structure and molecular mobility of peri- and infarct zones post-MI is rather limited. The main objective of this work was to explore the spatiotemporal biochemical and biophysical alterations of key cardiac components post-MI. The FTIR spectra of healthy and remote myocardial tissue shows amides A, I, II and III associated with proteins in freeze-died tissue as major absorptions bands. In infarcted myocardium, the spectrum of these main absorptions was deeply altered. FITR evidenced an increase of the amide A band and the distinct feature of the collagen specific absorption band at 1338cm-1 in the infarct area at 21days post-MI. At 21days post-MI, it also appears an important shift of amide I from 1646cm-1 to 1637cm-1 that suggests the predominance of the triple helical conformation in the proteins. The new spectra bands also indicate an increase in proteoglycans, residues of carbohydrates in proteins and polysaccharides in ischemic areas. Thermal analysis indicates a deep increase of unfreezable water/freezable water in peri- and infarcted tissues. In infarcted tissue is evidenced the impairment of myofibrillar proteins thermal profile and the emergence of a new structure. In conclusion, our results indicate a profound evolution of protein secondary structures in association with collagen deposition and reorganization of water involved in the scar maturation of peri- and infarct zones post-MI.

Serum microRNA-1 and microRNA-133a levels reflect myocardial steatosis in uncomplicated type 2 diabetes.

Using in vitro, in vivo and patient-based approaches, we investigated the potential of circulating microRNAs (miRNAs) as surrogate biomarkers of myocardial steatosis, a hallmark of diabetic cardiomyopathy. We analysed the cardiomyocyte-enriched miRNA signature in serum from patients with well-controlled type 2 diabetes and with verified absence of structural heart disease or inducible ischemia, and control volunteers of the same age range and BMI (N = 86), in serum from a high-fat diet-fed murine model, and in exosomes from lipid-loaded HL-1 cardiomyocytes. Circulating miR-1 and miR-133a levels were robustly associated with myocardial steatosis in type 2 diabetes patients, independently of confounding factors in both linear and logistic regression analyses (P < 0.050 for all models). Similar to myocardial steatosis, miR-133a levels were increased in type 2 diabetes patients as compared with healthy subjects (P < 0.050). Circulating miR-1 and miR-133a levels were significantly elevated in high-fat diet-fed mice (P < 0.050), which showed higher myocardial steatosis, as compared with control animals. miR-1 and miR-133a levels were higher in exosomes released from lipid-loaded HL-1 cardiomyocytes (P < 0.050). Circulating miR-1 and miR-133a are independent predictors of myocardial steatosis. Our results highlight the value of circulating miRNAs as diagnostic tools for subclinical diabetic cardiomyopathy.

Lipopolysaccharide downregulates CD91/low-density lipoprotein receptor-related protein 1 expression through SREBP-1 overexpression in human macrophages.

Sterol regulatory element-binding proteins (SREBPs) negatively modulate the expression of the CD91/low-density lipoprotein receptor-related protein (LRP1), a carrier and signaling receptor that mediates the endocytosis of more than 40 structurally and functionally distinct ligands. The aim of this work was to analyze whether lipopolysaccharide (LPS) can regulate LRP1 expression through SREBPs in human monocyte-derived macrophages (HMDM). LPS led to LRP1 mRNA and protein inhibition in a dose- and time-dependent manner. Concomitantly, a strong upregulation of SREBP-1 mRNA and SREBP-1 nuclear protein levels was observed in LPS-treated HMDM. The specific silencing of SREBP-1 efficiently prevented LRP1 reduction caused by LPS. SREBP-1 mRNA and nuclear protein levels remained high in HMDM treated with LPS unexposed or exposed to LDL. Native (nLDL) or aggregated LDL (agLDL) per se downregulated SREBP-2 expression levels and increased LRP1 expression. However, lipoproteins did not significantly alter the effect of LPS on SREBP-1 and LRP1 expression. Collectively, these data support that lipoproteins and LPS exert their modulatory effect on LRP1 expression through different SREBP isoforms, SREBP-2 and SREBP-1, respectively. These results highlight a crucial role of SREBP-1 as a mediator of the downregulatory effects of LPS on LRP1 expression in human macrophages, independently of the absence or presence of modified lipoproteins.