INTRODUCTION AND OBJECTIVES:Early-onset nonsyndromic cardiomyopathies (eoNSCM) are rare in pediatrics and are often associated with cardiac events (CE). The prognostic impact of multiple genetic variants in eoNSCM remains incompletely characterized. This study aimed to describe clinical outcomes in a pediatric cohort with eoNSCM and to analyze their association with genetic burden. METHODS:Single-center retrospective study analyzing clinical and genetic data from patients with eoNSCM. The primary outcome was the occurrence of CE: ventricular tachycardia or fibrillation, appropriate implantable cardioverter-defibrillator shocks, cardiac arrest or sudden cardiac death, heart failure stages C and D, or heart transplantation. RESULTS:From 2014 to 2024, 202 pediatric patients were evaluated for cardiomyopathy, of whom 84 were diagnosed with eoNSCM (36.9% female; median age at onset, 13 [interquartile range, 2.5-15] years. Diagnoses included 53 hypertrophic cardiomyopathies (63%), 21 dilated cardiomyopathies (25%), and 10 arrhythmogenic cardiomyopathies (12%). A conclusive genetic diagnosis was obtained in 52 of 84 (62%). Twenty-four patients (29%) experienced a significant CE, of whom 19 of 24 (79%) carried multiple genetic variants. Children with multiple variants exhibited a significantly higher risk of CE compared with carriers of a single causal variant (HR, 7.27; 95%CI, 2.47-21.44; P < .001). The highest risk was observed in patients carrying 2 pathogenic or likely pathogenic variants (P < .001). In dilated cardiomyopathy, adding baseline phenotype (left ventricular dilation and systolic dysfunction) to a genetics-only model improved discrimination for CE (integrated discrimination improvement, 0.528; 95%CI, 0.312-0.683; P < .001). CONCLUSIONS:Pediatric eoNSCM shows a high prevalence of rare variants. In this cohort, a higher genetic burden was associated with an increased risk of CE.

Background/Objectives: Acute heart failure (AHF) is a leading cause of hospitalization and mortality among very old patients, yet this group is underrepresented in prognostic studies. Carbohydrate antigen 125 (CA125) has emerged as a potential biomarker of congestion and inflammation, but its value in patients aged 80 years and over remains unclear. We aimed to evaluate the prognostic value of plasma CA125 measured at admission for 12-month all-cause mortality and the composite outcome of mortality or heart failure (HF) readmission in very elderly patients hospitalized for AHF. Methods: We conducted a prospective observational study of patients aged ≥80 years admitted to an acute geriatric unit for AHF. CA125 and NT-proBNP were measured within 24 h of admission. Outcomes were assessed at 12 months. Survival analyses were performed using Kaplan-Meier curves, Cox regression models, and restricted cubic splines. Results: A total of 210 patients (mean age 89.8 ± 5.3 years; 75.3% females; 88.1% frail) were recruited. During the one-year follow-up, 70 deaths (37.2%) and 68 HF hospital readmissions (36.1%) were recorded. Patients in the highest CA125 tertile had an increased cumulative mortality risk (log-rank p = 0.061). A CA125 value ≥ 100 U/mL independently predicted both mortality (HR 1.88, 95% CI 1.15-3.09; p = 0.012) and the composite endpoint (HR 1.54, 95% CI 1.04-2.29; p = 0.031). Measures of functional dependence and frailty demonstrated greater discriminative ability than biomarkers. Conclusions: In very elderly patients hospitalized for AHF, elevated CA125 at admission independently predicted 12-month mortality and HF readmission. CA125 provides complementary prognostic information to geriatric assessment and may support risk stratification in this vulnerable population.

Introducción y objetivos Las miocardiopatías no sindrómicas de inicio precoz (ipMCNS) son poco frecuentes y a menudo se asocian con episodios cardiacos (EC). Aún no se ha caracterizado por completo el impacto pronóstico de las múltiples variantes genéticas en las ipMCNS. El objetivo de este estudio fue describir los resultados clínicos en una cohorte pediátrica con ipMCNS y analizar su asociación con la carga genética.Métodos Estudio retrospectivo unicéntrico de análisis de datos clínicos y genéticos de ipMCNS. El resultado primario fue la aparición de EC: taquicardia/fibrilación ventricular, descargas apropiadas de desfibrilador cardiaco implantable, paro/muerte súbita cardiaca, insuficiencia cardiaca en estadios C y D, y trasplante cardiaco.Resultados Entre 2014-2024, se evaluó a 202 niños por miocardiopatía y 84 presentaron una ipMCNS (el 36,9% eran mujeres; edad mediana de inicio de 13 años [rango intercuartílico, 2,5-15]). Los diagnósticos incluyeron 53 miocardiopatías hipertróficas (63%), 21 miocardiopatías dilatadas (25%) y 10 miocardiopatías arritmogénicas (12%). Se obtuvo un resultado genético concluyente en 52/84 (62%). Veinticuatro (29%) presentaron un EC significativo, de los cuales 19/24 (79%) eran portadores de múltiples variantes genéticas. Estos pacientes exhibieron un riesgo significativamente mayor de EC que los portadores de una única variante causal (HR = 7,27; IC95%, 2,47-21,44; p < 0,001). El mayor riesgo se observó en portadores de 2 variantes patógenas/probablemente patógenas (p < 0,001). En miocardiopatía dilatada, la incorporación del fenotipo basal (dilatación ventricular izquierda y disfunción sistólica) al modelo basado únicamente en genética mejoró la discriminación para EC (mejora integrada de la discriminación de 0,528; IC95%, 0,312-0,683; p < 0,001).Conclusiones Las ipMCNS en pediatría presentan una mayor carga genética que la que debuta en la edad adulta, con una contribución notable de múltiples variantes genéticas al riesgo de EC.

Dilated cardiomyopathy caused by variants in the LMNA gene leads to malignant arrhythmogenic events, faster phenotype progression and high risk of sudden cardiac death. The pathophysiological mechanisms triggering disease progression remains poorly understood. We investigated the mRNA and miRNA transcriptome in the myocardial tissue of 50-week-old LMNAR249W mice developing dilated cardiomyopathy. We found 2148 genes and 53 miRNAs that were differentially expressed in LMNAR249W hearts. Gene ontology and pathway enrichments showed that differentially expressed genes were enriched mainly for fatty acid metabolism, muscle contraction, cell adhesion and dilated cardiomyopathy pathways. The miRNA-mRNA interactions analysis identified 2197 miRNA-target pairs with an anti-correlation between differentially expressed genes and miRNAs. Gene ontology and pathway enrichments revealed that the most significant functions of miRNA targets are mainly related to heart development, cardiac muscle contraction, fatty acid β-oxidation, cell adhesion and calcium binding pathways, among others. Our study provides new insights into the molecular mechanisms that determine dilated cardiomyopathy due to pathogenic variants in the LMNA gene, and identified several target pairs that are of potential interest for further studies.

IntroductionCardiovascular diseases (CVDs) are the leading cause of death globally, taking an estimated 17.9 million lives each year. Most heart cardiomyopathies result in an increased need for protein production that translates into an increased endoplasmic reticulum stress and therefore in the activation of the unfolded protein response pathway (UPR). The sustained activation of this pathway produces cell death and worsens the course of the disease. The role of lncRNAs in UPR signalling and their impact in several cardiomyopathies is beginning to be addressed.MethodsTo conduct our study we have performed real time PCR (qPCR), immunochemistry (IMQ), SeaHorse mithocondrial activity, Western blot (WB), Mass spectrometry (MS) and cell viability analysis.ResultsOur results demonstrate a sex-dependent regulation of Walar, Walaa, Wallrd, Walrad and Walras lncRNAs in different dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) murine experimental models. Functional assays demonstrated that Walras overexpression leads to unfolded protein response (UPR) pathway activation and increased apoptosis, and additionally it also impairs mitochondrial function. Mechanistically, Walras physically interacts with calumenin (CALU), repressing its protein levels by promoting proteosomal degradation. Finally, we proved that APO02340.1, a Walras human homologue exerts a similar role.DiscussionOur data demonstrate that Walras and APO02340.1 modulate UPR associated apoptosis by regulating CALU protein turnover and thus acting as deletereous factors in several cardiomyophaties.

[This corrects the article DOI: 10.3389/fphys.2026.1740128.].

A conclusive and early diagnosis of cardiomyopathy is essential for implementing preventive therapeutic measures and, therefore, reducing the risk of malignant arrhythmias and even sudden cardiac death. Occasionally, this lethal event can be the first manifestation of cardiomyopathy, with or without a clear structural defect. In cases of sudden death, especially in young patients, the autopsy may be ambiguous and therefore lack a definitive diagnosis of cardiomyopathy, although it can sometimes identify signs that lead us to suspect it. This is one of the current challenges of forensic science, where occult cardiomyopathies often remain unidentified without additional testing that is not routinely included in current forensic protocols. In this protocol, it is crucial to perform a molecular autopsy but also to include additional data, especially family history, that will help conclude or at least suspect this entity. Obtaining this diagnosis or suspicion of concealed cardiomyopathy not only provides an answer to the unexpected death but also helps the relatives determine the cause of death. In addition, physicians should initiate a family assessment to identify other family members who may be at risk early and adopt personalized preventive measures.

Background/Objectives: Aortic stenosis (AS) is the most common valvular pathology in the geriatric population and is the primary cause of valve replacement. However, misdiagnoses and delays in treatment are common due to comorbidities, frailty, and sedentary lifestyles among elderly individuals. MicroRNAs (miRNAs) are highly conserved molecular regulators involved in various cellular processes and have gained recognition as reliable biomarkers in cardiovascular diseases. In the present study, we evaluated plasma miRNAs as potential biomarkers for the early diagnosis of AS in the geriatric population to identify early therapeutic strategies. Methods: This prospective, case–control study included 87 individuals over 75 years of age. The participants were divided into AS (n = 58) and control (n = 29) groups. Results: Fifty-four miRNAs were differentially expressed between patients with AS and controls. Among those genes, 29 were upregulated and 25 were downregulated in patients with AS relative to controls. We selected seven candidate genes (miR-185-5p, miR-143-3p, miR-370-3p, let-7d-3p, miR-452-5p, miR-6787-3p, and miR-21-3p) for experimental validation by qRT–PCR. Only miR-143-3p and miR-452-5p were significantly upregulated in the plasma of patients with AS compared with controls. We developed a multiparametric model by combining the two-miRNA signature with echocardiographic parameters (left ventricular ejection fraction, stroke volume, and global longitudinal strain) to increase diagnostic power; this model yielded sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) values of 78.2%, 70.7%, and 0.837, respectively. Conclusions: In clinical practice, the use of a multiparametric model involving this set of miRNAs combined with echocardiographic variables may improve the accuracy of AS diagnosis and risk stratification.

Genetic analysis identified the cause of the disease in inherited arrhythmogenic syndromes. A clinically actionable genetic diagnosis requires an accurate interpretation following the current guidelines. Practically half of the genetic diagnoses remain inconclusive due to the identification of variants of uncertain significance. An update can help shed light on uncertain results. No specific time frame has been set for updating an ambiguous diagnosis. We carried out an analysis of the available reclassification/reinterpretation data concerning genetic diagnosis in inherited arrhythmogenic syndromes. We aim to determine an appropriate interval for updating a conclusive classification. Genetic diagnoses achieved without following current guidelines should be updated immediately. An ambiguous result obtained following the current guidelines should be updated no more than 5 years after the first analysis. There are still questions to be resolved regarding the legal responsibility or who should assume the economic cost of updating a genetic diagnosis.

Excess lipid accumulation in the heart is associated with lipotoxicity and cardiac dysfunction due to excessive fatty acid oxidation. Peroxisome proliferator-activated receptor gamma (PPARγ) modulates the expression of key molecules involved in the FA metabolic pathway. Cardiomyocyte-specific overexpression of PPARγ causes dilated cardiomyopathy associated with lipotoxicity in mice. miR-130b-3p has been shown to be downregulated in the plasma of idiopathic dilated cardiomyopathy patients, but its role in modulating cardiomyocyte lipotoxicity via PPARγ remains unclear. Our objective was to investigate the protective role of miR-130b-3p against palmitate-induced lipotoxicity in cardiomyocytes through the modulation of the PPARγ signaling pathway. Human cardiomyoblasts were treated with palmitate. Intracellular lipid accumulation and expression of PPARγ and its downstream targets (CD36, FABP3, CAV1, VLDLR) were analyzed. Mitochondrial oxidative stress was assessed via MitoTracker Green and Redox Sensor Red staining and expression of CPT1B and SOD2. Endoplasmic reticulum stress and apoptosis were determined by examining GRP78, ATF6, XBP1s, CHOP, and caspase-3 expression. miR-130b-3p overexpression was achieved using transfection methods, and its effect on these parameters was evaluated. Luciferase assays were used to confirm PPARγ as a direct target of miR-130b-3p. Palmitate treatment led to increased lipid accumulation and upregulation of PPARγ and its downstream targets in human cardiomyoblasts. Palmitate also increased mitochondrial oxidative stress, endoplasmic reticulum stress and apoptosis. miR-130b-3p overexpression reduced PPARγ expression and its downstream signaling, alleviated mitochondrial oxidative stress and decreased endoplasmic reticulum stress and apoptosis in palmitate-stimulated cardiomyoblasts. Luciferase assays confirmed PPARγ as a direct target of miR-130b-3p. Our findings suggest that miR-130b-3p plays a protective role against palmitate-induced lipotoxicity in cardiomyocytes by modulating the PPARγ signaling pathway.

Background/Objectives: Inherited arrhythmogenic syndromes comprise a heterogenic group of genetic entities that lead to malignant arrhythmias and sudden cardiac death. Genetic testing has become crucial to understand the disease etiology and allow for the early identification of relatives at risk; however, it requires an accurate interpretation of the data to achieve a clinically actionable outcome. This is particularly challenging for the large number of rare variants obtained by current high-throughput techniques, which are mostly classified as of unknown significance. Methods: In this work, we present a new algorithm for the genetic interpretation of the remaining rare variants in order to shed light on their potential clinical implications and reduce the burden of unknown significance. Results: Our study illustrates the potential utility of our individualized comprehensive stepwise analyses focused on the rare variants associated with IAS, which are currently classified as ambiguous, to further determine their trends towards pathogenicity or benign traits. Conclusions: We advocate for personalized disease-focused population frequency data and family segregation analyses for all rare variants that remain ambiguous to further clarify their role. The current ambiguity should not influence medical decisions, but a potential deleterious role would suggest a closer clinical follow-up and frequent genetic data review for a more personalized clinical approach.

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.

Arrhythmogenic cardiomyopathy is an inherited entity characterized by irregular cell-cell adhesion, cardiomyocyte death and fibro-fatty replacement of ventricular myocytes, leading to malignant ventricular arrythmias, contractile dysfunction and sudden cardiac death. Pathogenic variants in genes that encode desmosome are the predominant cause of arrhythmogenic cardiomyopathy. Moreover, signalling pathways such as Wnt/ß-catenin and transforming growth factor-β have been involved in the disease progression. However, still little is known about the molecular pathophysiological mechanisms that underlie arrhythmogenic cardiomyopathy pathogenesis. We used mRNA and small RNA sequencing to analyse the transcriptome of health and arrhythmogenic cardiomyopathy of autopsied human hearts. Our results showed 697 differentially expressed genes and eight differentially expressed miRNAs. Functional enrichment revealed mitochondrial respiratory-related pathways, impaired response to oxidative stress, apoptotic signalling pathways and inflammatory response-related and extracellular matrix response pathways. Furthermore, analysis of the miRNA-mRNA interactome identified eleven negatively correlated miRNA-target pairs for arrhythmogenic cardiomyopathy. Our finding revealed novel arrhythmogenic cardiomyopathy-related miRNAs with important regulatory function in disease pathogenesis, highlighting their value as potential key targets for therapeutic approaches.

Sudden cardiac death is a rare but socially devastating event, especially if occurs in young people. Usually, this unexpected lethal event occurs during or just after exercise. One of the leading causes of sudden cardiac death is inherited arrhythmogenic syndromes, a group of genetic entities characterised by incomplete penetrance and variable expressivity. Exercise can be the trigger for malignant arrhythmias and even syncope in population with a genetic predisposition, being sudden cardiac death as the first symptom. Due to genetic origin, family members must be clinically assessed and genetically analysed after diagnosis or suspected diagnosis of a cardiac channelopathy. Early identification and adoption of personalised preventive measures is crucial to reduce risk of arrhythmias and avoid new lethal episodes. Despite exercise being recommended by the global population due to its beneficial effects on health, particular recommendations for these patients should be adopted considering the sport practised, level of demand, age, gender, arrhythmogenic syndrome diagnosed but also genetic diagnosis. Our review focuses on the role of genetic background in sudden cardiac death during exercise in child and young population.

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.

Genetic testing is recommended in the diagnosis of short QT syndrome. This rare inherited lethal entity is characterized by structural normal hearts with short QT intervals in the electrocardiogram. Few families diagnosed with this arrhythmogenic disease have been reported worldwide so far, impeding a comprehensive understanding of this syndrome. Unraveling the origin of the disease helps to the early identification of genetic carriers at risk. However, only rare variants with a definite deleterious role should be actionable in clinical practice. Our aim was to perform a comprehensive update and reinterpretation, according to the American College of Medical Genetics and Genomics recommendations of all rare variants currently associated with short QT syndrome. We identified 34 rare variants. Reanalysis showed that only nine variants played a deleterious role associated with a definite short QT syndrome phenotype. These variants were located in the four main genes: KCNQ1, KCNH2, KCNJ2 or SLC4A3. Additional rare variants located in other genes were associated with other conditions with phenotypic shortened QT intervals, but not definite diagnosis of short QT syndrome. Periodically updating of rare variants, especially those previously classified as unknown, helps to clarify the role of rare variants and translate genetic data into clinical practice.

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.

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.

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.