Plasma microrna expression profile for reduced ejection fraction in dilated cardiomyopathy

The left ventricular (LV) ejection fraction (EF) is key to prognosis in dilated cardiomyopathy (DCM). Circulating microRNAs have emerged as reliable biomarkers for heart diseases, included DCM. Clinicians need improved tools for greater clarification of DCM EF categorization, to identify highrisk patients. Thus, we investigated whether microRNA profiles can categorize DCM patients based on their EF. 179-differentially expressed circulating microRNAs were screened in two groups: (1) non-idiopathic DCM; (2) idiopathic DCM. Then, 26 microRNAs were identified and validated in the plasma of ischemic-DCM (n = 60), idiopathic-DCM (n = 55) and healthy individuals (n = 44). We identified fourteen microRNAs associated with echocardiographic variables that differentiated idiopathic DCM according to the EF degree. A predictive model of a three-microRNA (miR-130b-3p, miR-150-5p and miR-210-3p) combined with clinical variables (left bundle branch block, left ventricle end-systolic dimension, lower systolic blood pressure and smoking habit) was obtained for idiopathic DCM with a severely reduced-EF. The receiver operating characteristic curve analysis supported the discriminative potential of the diagnosis. Bioinformatics analysis revealed that miR-150-5p and miR-210-3p target genes might interact with each other with a high connectivity degree. In conclusion, our results revealed a three-microRNA signature combined with clinical variables that highly discriminate idiopathic DCM categorization. This is a potential novel prognostic biomarker with high clinical value

Elderly Population with COVID-19 and the Accuracy of Clinical Scales and D-Dimer for Pulmonary Embolism: The OCTA-COVID Study

Background: Elderly COVID-19 patients have a high risk of pulmonary embolism (PE), but factors that predict PE are unknown in this population. This study assessed the Wells and revised Geneva scoring systems as predictors of PE and their relationships with D-dimer (DD) in this population. Methods: This was a longitudinal, observational study that included patients 75 years old with COVID-19 and suspected PE. The performances of theWells score, revised Geneva score and DD levels were assessed. The combinations of the DD level and the clinical scales were evaluated using positive rules for higher specificity. Results: Among 305 patients included in the OCTA-COVID study cohort, 50 had suspected PE based on computed tomography pulmonary arteriography (CTPA), and the prevalence was 5.6%. The frequencies of PE in the low-, intermediate- and high-probability categories were 5.9%, 88.2% and 5.9% for the Geneva model and 35.3%, 58.8% and 5.9% for the Wells model, respectively. The DD median was higher in the PE group (4.33 mg/L; interquartile range (IQR) 2.40–7.17) than in the no PE group (1.39 mg/L; IQR 1.01–2.75) (p < 0.001). The area under the curve (AUC) for DD was 0.789 (0.652–0.927). After changing the cutoff point for DD to 4.33 mg/L, the specificity increased from 42.5% to 93.9%. Conclusions: The cutoff point DD > 4.33 mg/L has an increased specificity, which can discriminate false positives. The addition of the DD and the clinical probability scales increases the specificity and negative predictive value, which helps to avoid unnecessary invasive tests in this population

Predictive Factors of Pulmonary Embolism in Older Patients with SARS-CoV-2: The OCTA-COVID-19 Study

Background: The risk of pulmonary embolism (PE) has not been studied in older patients affected by COVID-19. We aimed to assess PE incidence and risk factors in a population of older patients infected with SARS-CoV-2. Methods: An ambispective, observational cohort study. A total of 305 patients >= 75 years old had the SARS-CoV-2 infection from March to May 2020. The incidence rate of PE was estimated as the proportion of new cases within the whole sample. Youden's index was used to assess the cutoff point of D-dimer. To select factors associated with the risk of PE, time-to-event analyses were performed using cause-specific hazard models. Results: In total, 305 patients with a median age of 87 years (62.3% female) were studied; 67.9% were referred from nursing homes and 90.4% received any type of anticoagulation. A total of 64.9% showed frailty and 44% presented with dementia. The PE incidence was 5.6%. The cutoff value of a D-dimer level over 2.59 mg/L showed a sensitivity of 82.4% and specificity of 73.8% in discriminating a PE diagnosis. In the multivariate analysis, the factors associated with PE were previous oncological events and D-dimer levels. Conclusions: The PE incidence was 5.6%, and major risk factors for PE were oncological antecedents and increased plasma D-dimer levels.This work was partially supported by grants (to M.Q.-F., J.G.-P.) from the "New announcement for extraordinary initiative fund UAX-Santander COVID-19," Alfonso X el Sabio University

Circulating circRNA as biomarkers for dilated cardiomyopathy etiology

Dilated cardiomyopathy (DCM) is the third most common cause of heart failure. The multidisciplinary nature of testing - involving genetics, imaging, or cardiovascular techniques - makes its diagnosis challenging. Novel and reliable biomarkers are needed for early identification and tailored personalized management. Peripheral circular RNAs (circRNAs), a leading research topic, remain mostly unexplored in DCM. We aimed to assess whether peripheral circRNAs are expressed differentially among etiology-based DCM. The study was based on a case-control multicentric study. We enrolled 130 subjects: healthy controls (n = 20), idiopathic DCM (n = 30), ischemic DCM (n = 20), and familial DCM patients which included pathogen variants of (i) LMNA gene (n = 30) and (ii) BCL2-associated athanogene 3 (BAG3) gene (n = 30). Differentially expressed circRNAs were analyzed in plasma samples by quantitative RT-PCR and correlated to relevant systolic and diastolic parameters. The pathophysiological implications were explored through bioinformatics tools. Four circRNAs were overexpressed compared to controls: hsa_circ_0003258, hsa_circ_0051238, and hsa_circ_0051239 in LMNA-related DCM and hsa_circ_0089762 in the ischemic DCM cohort. The obtained areas under the curve confirm the discriminative capacity of circRNAs. The circRNAs correlated with some diastolic and systolic echocardiographic parameters with notable diagnostic potential in DCM. Circulating circRNAs may be helpful for the etiology-based diagnosis of DCM as a non-invasive biomarker. Key messages The limitations of cardiac diagnostic imaging and the absence of a robust biomarker reveal the need for a diagnostic tool for dilated cardiomyopathy (DCM). The circular RNA (circRNA) expression pattern is paramount for categorizing the DCM etiologies. Our peripheral circRNAs fingerprint discriminates between various among etiology-based DCM and correlates with some echocardiographic parameters. We provide a potential non-invasive biomarker for the etiology-based diagnosis of LMNA-related DCM and ischemic DCM.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by grants in the framework of the European Regional Development Fund (ERDF) Integrated Territorial Initiative (ITI PI0048-2017 and ITI0033_2019), a clinical research grant from the Spanish Society of Cardiology for Basic Research in cardiology (PI0012_2019), COST (European Cooperation in Science and Technology) Action EUCardioRNA CA17129, and the Portuguese Foundation for Science and Technology (FCT) under the framework of the research grant PTDC-MED-GEN-29389-2017

Relationship between lipoprotein (a) and micro/macro complications in type 2 diabetes mellitus: a forgotten target.

OBJECTIVES: Increased lipoprotein (a) serum concentrations seems to be a cardiovascular risk factor; this has not been confirmed in extracoronary atherosclerosis complications. We therefore wished to gain a deeper insight into relationship between the plasma concentrations of lipoprotein (a) and the micro- and macro-vascular complications of type 2 diabetes mellitus and to identify possible differences in this association. METHODS: This is a descriptive observational cross-sectional study. Two-hundred and seventeen elderly patients with type 2 diabetes mellitus were included from the internal medicine outclinic. Anthropometric data, analytical data (insulin reserve, basal and postprandial peptide C, glycosylated hemoglobin, renal parameters, lipid profile and clinical data as hypertension, obesity, micro- and macrovascular complications were collected. RESULTS: Patients were grouped according to the type 2 diabetes mellitus time of evolution. The mean plasma concentration of lipoprotein (a) was 22.2 ± 17.3 mg/dL (22.1 ± 15.9 mg/dL for males, and 22.1 ± 18.4 mg/dL for females). Patients with hypertension, coronary heart disease, cerebrovascular accident, microalbuminuria and proteinuria presented a statistically significant increased level of lipoprotein (a). Similarly, the patients with hyperlipoprotein (a) (≥ 30 mg/dL) presented significantly increased levels of urea and total cholesterol. In the multivariate regression model, the level of lipoprotein (a) is positively correlated with coronary heart disease and diabetic nephropathy (P < 0.01 and P < 0.005, respectively). CONCLUSIONS: The elevation of plasma levels of lipoprotein (a) are associated with the development of coronary heart disease and diabe tic nephropathy. Therefore, we consider that the determination of lipoprotein (a) may be a prognostic marker of vascular complications in patients with type 2 diabetes mellitus

COVID-19 Mortality in Patients Aged 80 and over Residing in Nursing Homes&mdash;Six Pandemic Waves: OCTA-COVID Study

During the first COVID-19 pandemic wave in Spain, 50% of deaths occurred in nursing homes, making it necessary for some hospitals to support these facilities with the care of infected patients. This study compares origin, characteristics, and mortality of patients admitted with COVID-19 during six pandemic waves in the Hospital Central de la Cruz Roja in Madrid. It is a retrospective observational study of patients &ge;80 years old, admitted with an acute SARS-CoV-2 infection, with a total of 546 patients included, whose final outcome was death or discharge. During the first wave, those from nursing homes had a higher risk of death than those from home; during the two successive waves, the risk was higher for those from home; and in the last two waves, the risk equalized and decreased exponentially in both groups. Men had 72% higher risk of death than women. For each year of age, the risk increased by 4% (p = 0.036). For each Charlson index point, the risk increased by 14% (p = 0.019). Individuals in nursing homes, despite being older with higher comorbidity, did not show a higher overall lethality. The mortality decreased progressively in each successive wave due to high vaccination rates and COVID-19 control measures in this population

The Role of MicroRNAs in Dilated Cardiomyopathy: New Insights for an Old Entity.

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and systolic dysfunction. In most cases, DCM is progressive, leading to heart failure (HF) and death. This cardiomyopathy has been considered a common and final phenotype of several entities. DCM occurs when cellular pathways fail to maintain the pumping function. The etiology of this disease encompasses several factors, such as ischemia, infection, autoimmunity, drugs or genetic susceptibility. Although the prognosis has improved in the last few years due to red flag clinical follow-up, early familial diagnosis and ongoing optimization of treatment, due to its heterogeneity, there are no targeted therapies available for DCM based on each etiology. Therefore, a better understanding of the mechanisms underlying the pathophysiology of DCM will provide novel therapeutic strategies against this cardiac disease and their different triggers. MicroRNAs (miRNAs) are a group of small noncoding RNAs that play key roles in post-transcriptional gene silencing by targeting mRNAs for translational repression or, to a lesser extent, degradation. A growing number of studies have demonstrated critical functions of miRNAs in cardiovascular diseases (CVDs), including DCM, by regulating mechanisms that contribute to the progression of the disease. Herein, we summarize the role of miRNAs in inflammation, endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial dysfunction, autophagy, cardiomyocyte apoptosis and fibrosis, exclusively in the context of DCM

Unraveling the Etiology of Dilated Cardiomyopathy through Differential miRNA–mRNA Interactome

Dilated cardiomyopathy (DCM) encompasses various acquired or genetic diseases sharing a common phenotype. The understanding of pathogenetic mechanisms and the determination of the functional effects of each etiology may allow for tailoring different therapeutic strategies. MicroRNAs (miRNAs) have emerged as key regulators in cardiovascular diseases, including DCM. However, their specific roles in different DCM etiologies remain elusive. Here, we applied mRNA-seq and miRNA-seq to identify the gene and miRNA signature from myocardial biopsies from four patients with DCM caused by volume overload (VCM) and four with ischemic DCM (ICM). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used for differentially expressed genes (DEGs). The miRNA–mRNA interactions were identified by Pearson correlation analysis and miRNA target-prediction programs. mRNA-seq and miRNA-seq were validated by qRT-PCR and miRNA–mRNA interactions were validated by luciferase assays. We found 112 mRNAs and five miRNAs dysregulated in VCM vs. ICM. DEGs were positively enriched for pathways related to the extracellular matrix (ECM), mitochondrial respiration, cardiac muscle contraction, and fatty acid metabolism in VCM vs. ICM and negatively enriched for immune-response-related pathways, JAK-STAT, and NF-kappa B signaling. We identified four pairs of negatively correlated miRNA–mRNA: miR-218-5p-DDX6, miR-218-5p-TTC39C, miR-218-5p-SEMA4A, and miR-494-3p-SGMS2. Our study revealed novel miRNA–mRNA interaction networks and signaling pathways for VCM and ICM, providing novel insights into the development of these DCM etiologies

miR-16-5p Suppression Protects Human Cardiomyocytes against Endoplasmic Reticulum and Oxidative Stress-Induced Injury

Oxidative stress, defined as the excess production of reactive oxygen species (ROS) relative to antioxidant defense, plays a significant role in the development of cardiovascular diseases. Endoplasmic reticulum (ER) stress has emerged as an important source of ROS and its modulation could be cardioprotective. Previously, we demonstrated that miR-16-5p is enriched in the plasma of ischemic dilated cardiomyopathy (ICM) patients and promotes ER stress-induced apoptosis in cardiomyocytes in vitro. Here, we hypothesize that miR-16-5p might contribute to oxidative stress through ER stress induction and that targeting miR-16-5p may exert a cardioprotective role in ER stress-mediated cardiac injury. Analysis of oxidative markers in the plasma of ICM patients demonstrates that oxidative stress is associated with ICM. Moreover, we confirm that miR-16-5p overexpression promotes oxidative stress in AC16 cardiomyoblasts. We also find that, in response to tunicamycin-induced ER stress, miR-16-5p suppression decreases apoptosis, inflammation and cardiac damage via activating the ATF6-mediated cytoprotective pathway. Finally, ATF6 is identified as a direct target gene of miR-16-5p by dual-luciferase reporter assays. Our results indicate that miR-16-5p promotes ER stress and oxidative stress in cardiac cells through regulating ATF6, suggesting that the inhibition of miR-16-5p has potential as a therapeutic approach to protect the heart against ER and oxidative stress-induced injury

Emerging role of microRNAs in dilated cardiomyopathy: evidence regarding etiology.

Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease. This cardiac disorder is a major health problem due to its high prevalence, morbidity, and mortality. DCM is a complex disease with a common phenotype but heterogeneous pathological mechanisms. Early etiological diagnosis and prognosis stratification is crucial for the clinical management of the patient. Advances in imaging technology and genetic tests have provided useful tools for clinical practice. Nevertheless, the assessment of the disease remains challenging. Novel noninvasive indicators are still needed to assist in decision-making. microRNAs (miRNAs), a group of small noncoding RNAs, have been identified as key mediators of cell biology. They are found in a stable form in body fluids and their concentration is altered in response to stress. Previous research has suggested that the miRNA signature constitutes a novel source of noninvasive biomarkers for a wide array of cardiovascular diseases. Specifically, several studies have reported the potential role of miRNAs as clinical indicators among the etiologies of DCM. However, this field has not been reviewed in detail. Here, we summarize the evidence of intracellular and circulating miRNAs in DCM and their usefulness in the development of novel diagnostic, prognostic and therapeutic approaches, with a focus on DCM etiology. Although the findings are still preliminary, due to methodological and technical limitations and the lack of robust population-based studies, miRNAs constitute a promising tool to assist in the clinical management of DCM