Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy.

Dilated cardiomyopathy is a heterogeneous entity that leads to heart failure and malignant arrhythmias. Nearly 50% of cases are inherited; therefore, genetic analysis is crucial to unravel the cause and for the early identification of carriers at risk. A large number of variants remain classified as ambiguous, impeding an actionable clinical translation. Our goal was to perform a comprehensive update of variants previously classified with an ambiguous role, applying a new algorithm of already available tools. In a cohort of 65 cases diagnosed with dilated cardiomyopathy, a total of 125 genetic variants were classified as ambiguous. Our reanalysis resulted in the reclassification of 12% of variants from an unknown to likely benign or likely pathogenic role, due to improved population frequencies. For all the remaining ambiguous variants, we used our algorithm; 60.9% showed a potential but not confirmed deleterious role, and 24.5% showed a potential benign role. Periodically updating the population frequencies is a cheap and fast action, making it possible to clarify the role of ambiguous variants. Here, we perform a comprehensive reanalysis to help to clarify the role of most of ambiguous variants. Our specific algorithms facilitate genetic interpretation in dilated cardiomyopathy.

Exploring miRNA-target gene pair detection in disease with coRmiT.

A wide range of approaches can be used to detect micro RNA (miRNA)-target gene pairs (mTPs) from expression data, differing in the ways the gene and miRNA expression profiles are calculated, combined and correlated. However, there is no clear consensus on which is the best approach across all datasets. Here, we have implemented multiple strategies and applied them to three distinct rare disease datasets that comprise smallRNA-Seq and RNA-Seq data obtained from the same samples, obtaining mTPs related to the disease pathology. All datasets were preprocessed using a standardized, freely available computational workflow, DEG_workflow. This workflow includes coRmiT, a method to compare multiple strategies for mTP detection. We used it to investigate the overlap of the detected mTPs with predicted and validated mTPs from 11 different databases. Results show that there is no clear best strategy for mTP detection applicable to all situations. We therefore propose the integration of the results of the different strategies by selecting the one with the highest odds ratio for each miRNA, as the optimal way to integrate the results. We applied this selection-integration method to the datasets and showed it to be robust to changes in the predicted and validated mTP databases. Our findings have important implications for miRNA analysis. coRmiT is implemented as part of the ExpHunterSuite Bioconductor package available from https://bioconductor.org/packages/ExpHunterSuite.

Role of microRNAs in arrhythmogenic cardiomyopathy: translation as biomarkers into clinical practice.

Arrhythmogenic cardiomyopathy is a rare inherited entity, characterized by a progressive fibro-fatty replacement of the myocardium. It leads to malignant arrhythmias and a high risk of sudden cardiac death. Incomplete penetrance and variable expressivity are hallmarks of this arrhythmogenic cardiac disease, where the first manifestation may be syncope and sudden cardiac death, often triggered by physical exercise. Early identification of individuals at risk is crucial to adopt protective and ideally personalized measures to prevent lethal episodes. The genetic analysis identifies deleterious rare variants in nearly 70% of cases, mostly in genes encoding proteins of the desmosome. However, other factors may modulate the phenotype onset and outcome of disease, such as microRNAs. These small noncoding RNAs play a key role in gene expression regulation and the network of cellular processes. In recent years, data focused on the role of microRNAs as potential biomarkers in arrhythmogenic cardiomyopathy have progressively increased. A better understanding of the functions and interactions of microRNAs will likely have clinical implications. Herein, we propose an exhaustive review of the literature regarding these noncoding RNAs, their versatile mechanisms of gene regulation and present novel targets in arrhythmogenic cardiomyopathy.

Value of NT-proBNP and Galectin-3 as Biomarkers in the Follow-Up of Asymptomatic Elderly Patients with Severe Aortic Stenosis.

Recognizing symptoms in elderly patients with severe aortic stenosis (AS) can be a challenge. Serum biomarkers such as Galectin-3 or N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are involved in remodeling and heart failure (HF) development and could support the diagnosis of AS. We set out to test the usefulness of NT-proBNP and Galectin-3 in predicting events in this population. We designed a prospective observational case-control study, including 50 asymptomatic patients older than 70 years, diagnosed with severe degenerative AS, and 50 control individuals. The NT-proBNP and Galectin-3 levels were measured. A follow-up was carried out at 12 months to determine the occurrence of hospital admission for HF, all-cause mortality or the appearance of symptoms. The patients with severe AS had higher Galectin-3 and NT-proBNP concentrations. The area under the receiver operating characteristic curve of the NT-proBNP was 0.812 (95% CI, 0.646-0.832), and that of the Galectin-3 was 0.633 (95% CI, 0.711-0.913). NT-proBNP was a good predictor of events [HR 3.45 (95% CI 1.32-9.03), p = 0.011]. A Kaplan-Meier analysis showed that the probability of freedom from events was significant in patients who exhibited a combination of higher NT-proBNP and Galectin-3 levels (log-rank p = 0.032). Therefore, NT-proBNP was the most reliable predictor of events in asymptomatic patients with severe AS. A combination of NT-proBNP and Galectin-3 levels may be vital in the clinical follow-up of these patients and in the decision-making process.

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death.

In the forensic medicine field, molecular autopsy is the post-mortem genetic analysis performed to attempt to unravel the cause of decease in cases remaining unexplained after a comprehensive forensic autopsy. This negative autopsy, classified as negative or non-conclusive, usually occurs in young population. In these cases, in which the cause of death is unascertained after a thorough autopsy, an underlying inherited arrhythmogenic syndrome is the main suspected cause of death. Next-generation sequencing allows a rapid and cost-effectives genetic analysis, identifying a rare variant classified as potentially pathogenic in up to 25% of sudden death cases in young population. The first symptom of an inherited arrhythmogenic disease may be a malignant arrhythmia, and even sudden death. Early identification of a pathogenic genetic alteration associated with an inherited arrhythmogenic syndrome may help to adopt preventive personalized measures to reduce risk of malignant arrhythmias and sudden death in the victim's relatives, at risk despite being asymptomatic. The current main challenge is a proper genetic interpretation of variants identified and useful clinical translation. The implications of this personalized translational medicine are multifaceted, requiring the dedication of a specialized team, including forensic scientists, pathologists, cardiologists, pediatric cardiologists, and geneticists.

Prevalence of transthyretin cardiac amyloidosis in elderly patients diagnosed with heart failure / Prevalencia de amiloidosis cardiaca por transtirretina en pacientes de edad avanzada con diagnóstico de insuficiencia cardiaca

Objective: There is increased interest in studying ATTR-CA, a pathology that primarily affects patients of geriatric age and is frequently underdiagnosed. We aim to establish the prevalence of ATTR-CA in a cohort of patients with a history of HFpEF and to describe its characteristics. Methods: We conducted a prospective observational study. Patients ≥75 years, clinical history of HFpEF, atrial dilation ≥34ml/m2 and left ventricular wall thickening >13mm, were included. Demographic and analytical parameters were collected, and a comprehensive geriatric assessment was performed, along with a transthoracic echocardiogram and cardiac scintigraphy. Finally, telephone follow-up was carried out at 6 and 12 months. Results: 50 patients were recruited, mean age 86±6 years, 54% women. Age and functional class (I–II vs. III–IV) were factors associated with presenting with ATTR-CA. Patients with positive scintigraphy had a median time to admission of 5.2 months (confidence interval [CI] 95% 0–10.9), while in those with negative scintigraphy, it was 12.2 months (95% CI 11.7–12.8); log-rank: p=0.064. Patients with positive scintigraphy had a median time to the combined endpoint (death and readmission) of 1.9 months (95% CI 0–6.1), and patients with negative scintigraphy of 11.9 months (95% CI 11.7–12); log-rank: p=0.027. Conclusions: ATTR-CA appears to be a prevalent etiology in elderly patients within the spectrum of HFpEF. Patients with a diagnosis of ATTR-CA had a shorter time to admission for HF and the combined event of death and admission than patients with a negative result on scintigraphy. (AU)

Objetivo: Existe un interés creciente por el estudio de AC-TTR, siendo esta una patología que afecta fundamentalmente a pacientes de edad avanzada y que es frecuentemente infradiagnosticada. Nuestro objetivo fue establecer la prevalencia de AC-TTR en una cohorte de pacientes con historia de ICFEp y describir sus características. Métodos: Estudio observacional prospectivo. Se incluyeron pacientes ≥75 años, con historia clínica de ICFEp, dilatación auricular ≥34ml/m2 y engrosamiento de la pared del ventrículo izquierdo >13mm. Se recogieron datos analíticos y demográficos, así como de la valoración geriátrica integral y se realizó un ecocardiograma transtorácico y una gammagrafía cardiaca. Finalmente se realizó seguimiento telefónico a los 6 y 12 meses. Resultados: Se incluyó a 50 pacientes, edad media 86±6 años, 54% mujeres. La edad y la clase funcional NYHA (I-II vs. III-IV) se asociaron con mayor riesgo de presentar AC-TTR. Los pacientes con gammagrafía positiva tuvieron una mediana de tiempo al ingreso de 5,2 meses (intervalo de confianza [IC] 95% 0-10,9), frente a aquellos con gammagrafía negativa que fue de 12,2 meses (IC 95% 11,7-12,8); log-rank: p=0,064. Los pacientes con gammagrafía positiva presentaron una mediana de tiempo al evento combinado (muerte y reingreso) de 1,9 meses (IC 95% 0-6,1), mientras que en aquellos con resultado negativo fue de 11,9 meses (IC 95% 11,7-12); log-rank: p=0.027. Conclusiones: La AC-TTR supone una etiología prevalente de insuficiencia cardiaca, dentro del espectro de la ICFEp, en pacientes de edad avanzada. Los individuos con diagnóstico de AC-TTR presentaron un menor tiempo al ingreso por insuficiencia cardiaca y al evento combinado de muerte y reingreso frente a aquellos pacientes con resultado negativo en la gammagrafía. (AU)

Reevaluation of ambiguous genetic variants in sudden unexplained deaths of a young cohort.

Sudden death cases in the young population remain without a conclusive cause of decease in almost 40% of cases. In these situations, cardiac arrhythmia of genetic origin is suspected as the most plausible cause of death. Molecular autopsy may reveal a genetic defect in up to 20% of families. Most than 80% of rare variants remain classified with an ambiguous role, impeding a useful clinical translation. Our aim was to update rare variants originally classified as of unknown significance to clarify their role. Our cohort included fifty-one post-mortem samples of young cases who died suddenly and without a definite cause of death. Five years ago, molecular autopsy identified at least one rare genetic alteration classified then as ambiguous following the American College of Medical Genetics and Genomics' recommendations. We have reclassified the same rare variants including novel data. About 10% of ambiguous variants change to benign/likely benign mainly because of improved population frequencies. Excluding cases who died before one year of age, almost 21% of rare ambiguous variants change to benign/likely benign. This fact makes it important to discard these rare variants as a cause of sudden unexplained death, avoiding anxiety in relatives' carriers. Twenty-five percent of the remaining variants show a tendency to suspicious deleterious role, highlighting clinical follow-up of carriers. Periodical reclassification of rare variants originally classified as ambiguous is crucial, at least updating frequencies every 5 years. This action aids to increase accuracy to enable and conclude a cause of death as well as translation into the clinic.

Prevalence of transthyretin cardiac amyloidosis in elderly patients diagnosed with heart failure.

OBJECTIVE: There is increased interest in studying ATTR-CA, a pathology that primarily affects patients of geriatric age and is frequently underdiagnosed. We aim to establish the prevalence of ATTR-CA in a cohort of patients with a history of HFpEF and to describe its characteristics. METHODS: We conducted a prospective observational study. Patients ≥75 years, clinical history of HFpEF, atrial dilation ≥34ml/m2 and left ventricular wall thickening >13mm, were included. Demographic and analytical parameters were collected, and a comprehensive geriatric assessment was performed, along with a transthoracic echocardiogram and cardiac scintigraphy. Finally, telephone follow-up was carried out at 6 and 12 months. RESULTS: 50 patients were recruited, mean age 86±6 years, 54% women. Age and functional class (I-II vs. III-IV) were factors associated with presenting with ATTR-CA. Patients with positive scintigraphy had a median time to admission of 5.2 months (confidence interval [CI] 95% 0-10.9), while in those with negative scintigraphy, it was 12.2 months (95% CI 11.7-12.8); log-rank: p=0.064. Patients with positive scintigraphy had a median time to the combined endpoint (death and readmission) of 1.9 months (95% CI 0-6.1), and patients with negative scintigraphy of 11.9 months (95% CI 11.7-12); log-rank: p=0.027. CONCLUSIONS: ATTR-CA appears to be a prevalent etiology in elderly patients within the spectrum of HFpEF. Patients with a diagnosis of ATTR-CA had a shorter time to admission for HF and the combined event of death and admission than patients with a negative result on scintigraphy.

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.

Impact of COVID-19 on Physical Activity and Lifestyles in Post-Confinement Sports Science Undergraduates.

The aim of this study was to assess whether the infection by SARS-CoV-2 has significantly influenced physical activity, diet, alcohol, and drug consumption habits, as well as the quality of life of students of the bachelor's degree in Physical Activity and Sports Sciences. For this purpose, an online survey was conducted, which included socio-demographic questions related to the COVID-19 disease. Physical activity was analyzed using the International Physical Activity Questionnaire (IPAQ), adherence to the Mediterranean diet using the PREDIMED questionnaire, alcohol consumption using the AUDIT questionnaire, and drug consumption using the DAST-10 questionnaire. Health-related quality of life was analyzed with the SF-12 questionnaire. Our results reveal that those who engaged in either vigorous physical activity or, on the contrary, very low-intensity physical activity, were affected by the SARS-CoV-2 disease, which reduced the average weekly time they spent on their type of activity. However, those who previously performed moderate activities have managed to stay on the same fitness level despite having suffered from SARS-CoV-2 disease (p = 0.433). In conclusion, general health is affected by suffering from the COVID-19 disease, inadequate eating habits, substance use, and the performance of vigorous or very low-intensity of physical activity.

A microRNA Signature for the Diagnosis of Statins Intolerance.

Atherosclerotic cardiovascular diseases (ASCVD) are the leading cause of morbidity and mortality in Western societies. Statins are the first-choice therapy for dislipidemias and are considered the cornerstone of ASCVD. Statin-associated muscle symptoms are the main reason for dropout of this treatment. There is an urgent need to identify new biomarkers with discriminative precision for diagnosing intolerance to statins (SI) in patients. MicroRNAs (miRNAs) have emerged as evolutionarily conserved molecules that serve as reliable biomarkers and regulators of multiple cellular events in cardiovascular diseases. In the current study, we evaluated plasma miRNAs as potential biomarkers to discriminate between the SI vs. non-statin intolerant (NSI) population. It is a multicenter, prospective, case-control study. A total of 179 differentially expressed circulating miRNAs were screened in two cardiovascular risk patient cohorts (high and very high risk): (i) NSI (n = 10); (ii) SI (n = 10). Ten miRNAs were identified as being overexpressed in plasma and validated in the plasma of NSI (n = 45) and SI (n = 39). Let-7c-5p, let-7d-5p, let-7f-5p, miR-376a-3p and miR-376c-3p were overexpressed in the plasma of SI patients. The receiver operating characteristic curve analysis supported the discriminative potential of the diagnosis. We propose a three-miRNA predictive fingerprint (let-7f, miR-376a-3p and miR-376c-3p) and several clinical variables (non-HDLc and years of dyslipidemia) for SI discrimination; this model achieves sensitivity, specificity and area under the receiver operating characteristic curve (AUC) of 83.67%, 88.57 and 89.10, respectively. In clinical practice, this set of miRNAs combined with clinical variables may discriminate between SI vs. NSI subjects. This multiparametric model may arise as a potential diagnostic biomarker with clinical value.

Early recruitable coronary collaterals preserve miocardial viability in late presentation infarctions.

BACKGROUND: Previous studies showed conflicting results regarding the contribution of coronary collateral circulation (CCC) to myocardial perfusion and function in the setting of myocardial infarction (MI). In the primary angioplasty era, the role of CCC in these studies may have been influenced by the effect of early reperfusion. The true impact of CCC could be clarified by studying its effect on nonreperfused patients. The aim of our study was to evaluate the effect of CCC on myocardial viability of late presentation MI. METHODS AND RESULTS: Between 2008 and 2019, we included 167 patients with a late presentation MI who had a complete angiographic occlusion in a major coronary artery in which myocardial viability of the culprit territory was assessed. Patients were divided according to the presence of angiographic early recruited CCC (ERCC) (Rentrop 2-3) or poor CCC (PCC) (Rentrop 0-1). A lower left ventricular ejection function (LVEF) at discharge (54.2 ± 9 vs. 47.9 ± 12; <0.01) and a more severe left ventricular wall motion abnormalities in the culprit territory were observed in PCC patients. The presence of ERCC was the main independent predictor of myocardial viability in late presentation MI (hazard ratio, 4.24; 95% confidence interval, 1.68-10.6; P < 0.001). At follow-up, wall motion score increased significantly (2.05 ± 0.16; P = 0.02) in patients with ERCC but not in PCC patients (0.07 ± 0.16; P = 0.4), and LVEF improvement was significantly higher in ERCC than in PCC patients (9.7 ± 2.6 vs. 3.8 ± 4.2; P = 0.02). CONCLUSION: The presence of ERCC was the main independent predictor of myocardial viability in late presentation MI.

Cardiac complications in a geriatric population hospitalized with COVID-19: The OCTA-COVID cohort / Complicaciones cardiacas en una población geritrica hospitalizada por COVID-19: La cohorte OCTA-COVID

Purpose: The geriatric population is especially vulnerable to coronavirus disease (COVID-19) and its potential complications. We sought to analyze the incidence of cardiological complications in an elderly population hospitalized for COVID-19.Methods: A prospective observational longitudinal that included patients ≥75 years of age with diagnosis of COVID-19 admitted to the Geriatric Department from March to May 2020. Epidemiological, geriatric, clinical and laboratory test variables were collected. Cardiovascular events, including de novo atrial fibrillation (AF), acute coronary syndrome (ACS), congestive heart failure (CHF), pulmonary embolism and in-hospital death, were documented. A follow-up was carried out at 12 months through a telephone interview as well as using electronic medical records, collecting cardiac events and mortality.Results:305 patients were included; 190 (62.3%) were female, with median age of 87 years (interquartile range (82–91)). More than half of the patients had a history of cardiac disease, with AF being the most common and affecting 85 (27.9%) patients. During hospitalization, 112 (36.7%) patients died. Eighty-nine (29.2%) patients presented cardiac complications. Acute heart failure was the most prevalent (46; 15.1%), followed by new-onset AF (20; 6.5%), pulmonary embolism (17; 5.6%), and ACS (5; 1.6%). Patients with cardiac complications had a longer hospital stay (p<0.001). During follow-up, 29 (15.1%) died, and 40 (20.8%) patients had a cardiovascular event being CHF the most prevalent complication (16.7%). (AU)

Introducción: La población geriátrica es especialmente vulnerable a la enfermedad por coronavirus (COVID-19) y sus posibles complicaciones. Nos propusimos analizar la incidencia de complicaciones cardiológicas en una población anciana hospitalizada por COVID-19.Métodos: Estudio longitudinal observacional prospectivo que incluyó a pacientes≥75 años con diagnóstico de COVID-19 ingresados en el Servicio de Geriatría de marzo a mayo de 2020. Se recogieron variables epidemiológicas, geriátricas, clínicas y de laboratorio. Se documentaron eventos cardiovasculares, que incluyen fibrilación auricular (FA) de novo, síndrome coronario agudo, insuficiencia cardíaca congestiva, embolia pulmonar y muerte intrahospitalaria. Se realizó un seguimiento a los 12 meses, mediante entrevista telefónica y accediendo a la historia clínica electrónica, recogiendo eventos cardíacos y mortalidad.Resultados: Se incluyeron 305 pacientes; 190 (62,3%) eran mujeres, con una mediana de edad de 87 años (rango intercuartílico: 82-91). Más de la mitad de los pacientes tenían antecedentes de enfermedad cardíaca, siendo la FA la más frecuente y afectando a 85 (27,9%) pacientes. Durante la hospitalización fallecieron 112 (36,7%) pacientes. Ochenta y nueve (29,2%) pacientes presentaron complicaciones cardíacas. La insuficiencia cardíaca congestiva aguda fue la más prevalente (46; 15,1%), seguida de la FA de nueva aparición (20; 6,5%), la embolia pulmonar (17; 5,6%) y el síndrome coronario agudo (5; 1,6%). Los pacientes con complicaciones cardíacas tuvieron una estancia hospitalaria más prolongada (p<0,001). Durante el seguimiento fallecieron 29 pacientes (15,1%) y 40 (20,8%) presentaron un evento cardiovascular, siendo la insuficiencia cardíaca congestiva la complicación más prevalente (16,7%). (AU)

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.

Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes.

The titin gene (TTN) is associated with several diseases, including inherited arrhythmias. Most of these diagnoses are attributed to rare TTN variants encoding truncated forms, but missense variants represent a diagnostic challenge for clinical genetics. The proper interpretation of genetic data is critical for translation into the clinical setting. Notably, many TTN variants were classified before 2015, when the American College of Medical Genetics and Genomics (ACMG) published recommendations to accurately classify genetic variants. Our aim was to perform an exhaustive reanalysis of rare missense TTN variants that were classified before 2015, and that have ambiguous roles in inherited arrhythmogenic syndromes. Rare missense TTN variants classified before 2015 were updated following the ACMG recommendations and according to all the currently available data. Our cohort included 193 individuals definitively diagnosed with an inherited arrhythmogenic syndrome before 2015. Our analysis resulted in the reclassification of 36.8% of the missense variants from unknown to benign/likely benign. Of all the remaining variants, currently classified as of unknown significance, 38.3% showed a potential, but not confirmed, deleterious role. Most of these rare missense TTN variants with a suspected deleterious role were identified in patients diagnosed with hypertrophic cardiomyopathy. More than 35% of the rare missense TTN variants previously classified as ambiguous were reclassified as not deleterious, mainly because of improved population frequencies. Despite being inconclusive, almost 40% of the variants showed a potentially deleterious role in inherited arrhythmogenic syndromes. Our results highlight the importance of the periodical reclassification of rare missense TTN variants to improve genetic diagnoses and help increase the accuracy of personalized medicine.

Clinical impact of rare variants associated with inherited channelopathies: a 5-year update.

A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated with inherited channelopathies originally classified 5 years ago and its clinical impact. In 2016, rare variants identified through genetic analysis were classified following the American College of Medical Genetics and Genomics' recommendations. Five years later, we have reclassified the same variants following the same recommendations but including new available data. Potential clinical implications were discussed. Our cohort included 49 cases of inherited channelopathies diagnosed in 2016. Update show that 18.36% of the variants changed classification mainly due to improved global frequency data. Reclassifications mostly occurred in minority genes associated with channelopathies. Similar percentage of variants remain as deleterious nowadays, located in main known genes (SCN5A, KCNH2 and KCNQ1). In 2016, 69.38% of variants were classified as unknown significance, but now, 53.06% of variants are classified as such, remaining the most common group. No management was modified after translation of genetic data into clinics. After 5 years, nearly 20% of rare variants associated with inherited channelopathies were reclassified. This supports performing periodic reanalyses of no more than 5 years since last classification. Use of newly available data is necessary, especially concerning global frequencies and family segregation. Personalized clinical translation of rare variants can be crucial to management if a significant change in classification is identified.

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 the Wells 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.

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.

Personalized Genetic Diagnosis of Congenital Heart Defects in Newborns.

Congenital heart disease is a group of pathologies characterized by structural malformations of the heart or great vessels. These alterations occur during the embryonic period and are the most frequently observed severe congenital malformations, the main cause of neonatal mortality due to malformation, and the second most frequent congenital malformations overall after malformations of the central nervous system. The severity of different types of congenital heart disease varies depending on the combination of associated anatomical defects. The causes of these malformations are usually considered multifactorial, but genetic variants play a key role. Currently, use of high-throughput genetic technologies allows identification of pathogenic aneuploidies, deletions/duplications of large segments, as well as rare single nucleotide variants. The high incidence of congenital heart disease as well as the associated complications makes it necessary to establish a diagnosis as early as possible to adopt the most appropriate measures in a personalized approach. In this review, we provide an exhaustive update of the genetic bases of the most frequent congenital heart diseases as well as other syndromes associated with congenital heart defects, and how genetic data can be translated to clinical practice in a personalized approach.

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.