Search Results (107)

Background/Objectives: PPP2R1A encodes the scaffold subunit Aα of protein phosphatase 2A (PP2A). Pathogenic variants cause Houge-Janssens syndrome 2, a rare neurodevelopmental disorder characterized by developmental delay, intellectual disability, epilepsy, and brain malformations. We systematically reviewed published cases to define the clinical spectrum, characterize the mutational landscape, and explore genotype–phenotype correlations. Methods: We conducted systematic searches of PubMed, Embase, and Web of Science from inception to March 2025, supplemented by GeneReviews and OMIM references. Studies reporting PPP2R1A variants with clinical data were included. Data extraction followed PRISMA guidelines, encompassing study characteristics, genetic findings, and phenotypic features. Results: We identified 16 studies representing 60 patients with PPP2R1A-related disorders. Twenty-six distinct pathogenic variants were identified; these were predominantly de novo heterozygous missense changes clustering within HEAT repeats 5–7. Recurrent hotspots included p.Arg182Trp (n = 12) and p.Arg183Gln (n = 5). Developmental delay and intellectual disability were universally present in all patients for whom data were available (100%, 58/58). Epilepsy occurred in 50.9% (29/57), and structural brain abnormalities in 83.1% (49/59), with corpus callosum abnormalities (40.7%, 24/59) and ventriculomegaly (32.2%, 19/59) being most frequent. Microcephaly was reported in 17.2% (10/58) and macrocephaly in 25.9% (15/58), while dysmorphic features were present in 53.4% (31/58). The phenotypic spectrum ranged from severe neonatal presentations with high mortality to milder neurodevelopmental courses, with prenatal manifestations including ventriculomegaly, corpus callosum abnormalities, and rare cardiac defects. Clear genotype–phenotype correlations emerged, with HEAT5 variants (p.Arg182Trp, p.Arg183Gln) associated with severe phenotypes and increased mortality, while p.Arg258His variants demonstrated comparatively milder courses. Conclusions: PPP2R1A-related disorders encompass a broad clinical spectrum ranging from lethal neonatal disease to survivable forms with variable neurodevelopmental outcomes. Prenatal features including ventriculomegaly and corpus callosum abnormalities enable early genetic diagnosis, informing reproductive counseling. Recognition of recurrent hotspot variants and their phenotype associations facilitates diagnosis, prognosis, and genetic counseling. These findings provide evidence-based guidance for clinical management and highlight the importance of variant-specific prognostication in this emerging neurodevelopmental disorder. Full article

Introduction: Platelet-derived growth factor receptor beta (PDGFRβ) is a key regulator of fibrogenesis. Non-invasive imaging of PDGFRβ expression may offer a novel approach to assess fibrotic remodeling, particularly in cardiac patients’ post-intervention, where fibrosis poses clinical risk. This study presents the GMP-compliant production of a novel PDGFRβ-targeted PET radiopharmaceutical, [⁶⁸Ga]Ga-DOTA-Z09591 ([⁶⁸Ga]Ga-ATH001), and its preclinical evaluation in mouse and human myocardial tissue, along with initial clinical imaging in patients with ST-elevation myocardial infarction (STEMI). Methods: The precursor was chemically synthesized and radiolabeled with gallium-68 using a fully automated, GMP-compatible system and a pharmaceutical-grade ⁶⁸Ge/⁶⁸Ga generator. Autoradiography, H&E, Sirius Red, Masson’s trichrome, and IHC staining were performed on infarcted mouse hearts and human myocardial biopsies. In vivo PET/MRI with [⁶⁸Ga]Ga-ATH001, ¹⁵O-H₂O, and gadolinium contrast was conducted in STEMI patients one week post-percutaneous coronary intervention. Results: [⁶⁸Ga]Ga-ATH001 was produced with high radiochemical yield and purity. Autoradiography demonstrated specific, receptor-mediated binding of [⁶⁸Ga]Ga-ATH001, co-localizing with PDGFRβ immunoreactivity, collagen deposition, and tissue damage. In STEMI patients, focal tracer uptake was observed in infarcted myocardium correlating with MRI-detected structural abnormalities and perfusion defects on ¹⁵O-H₂O PET. Uptake in unaffected myocardium was low and homogeneous, consistent with minimal physiological PDGFRβ expression. Conclusions: [⁶⁸Ga]Ga-ATH001 was successfully developed and validated for phase 0 clinical study. The tracer demonstrated PDGFRβ-specific binding in human fibrotic myocardium and enabled non-invasive detection of myocardial fibrogenic activity in STEMI patients. These findings support further clinical evaluation of [⁶⁸Ga]Ga-ATH001 as a targeted molecular imaging agent for early assessment of post-infarction fibrosis. Full article

Background: Dilated cardiomyopathy (DCM) is a myocardial disorder characterized by structural and functional abnormalities, in particular left or biventricular chamber dilatation and systolic dysfunction, occurring without evidence of coronary artery disease, hypertension, valvular disease, or congenital heart defects. It is a significant cause of sudden cardiac death, particularly in young individuals, often remaining undiagnosed until autopsy. Methods: A systematic review of the literature was conducted following PRISMA guidelines to revisit the main postmortem findings (gross, microscopic, and genetic) useful to perform the postmortem diagnosis of DCM. Scientific databases (PubMed and Scopus) were searched for articles published up to February 2025 describing postmortem findings in individuals diagnosed with DCM. Inclusion criteria were focused on studies reporting macroscopic cardiac findings, and microscopic and genetic variants identified postmortem or in related familial studies. Data were extracted and categorized to identify consistent diagnostic markers and to assess the frequency and relevance of genetic findings in autopsy-confirmed DCM cases. From 2081 initial records, 30 studies met inclusion criteria. Two reviewers independently performed study selection and data extraction, and methodological limitations of the included studies were considered qualitatively to inform the synthesis. Results: Common macroscopic features included increased heart weight (often > 350 g), dilated left or biventricular chambers, and thinning of the ventricular walls. Histologically, the most consistent findings were diffuse interstitial fibrosis, myocyte hypertrophy, and nuclear atypia. Particular attention was given to morphological features essential to distinguish between genetic and nongenetic forms of DCM and, thus, useful to perform a differential diagnosis with disease having a DCM-like pattern. Notably, truncating variants in genes such as TTN, FLNC, DSP, PKP2, and MYH7 were frequently reported, particularly in young decedents with no significant history of cardiac disease. However, only about half of reviewed studies included any form of genetic analysis, reflecting a significant gap in current practice for forensic pathologists. Conclusions: DCM may cause sudden death without prior symptoms, making genetic testing essential to uncover the diagnosis, especially in cases with a negative phenotype. Therefore, molecular autopsy combined with careful macroscopic and microscopic analysis can strengthen the forensic assessment. Full article

Background/Objectives: Mosaic variegated aneuploidy (MVA) is a rare chromosomal instability disorder. Biallelic variants in SMC5, a core component of the DNA repair machinery, cause Atelis Syndrome, characterized by severe growth failure and multi-system abnormalities. This study aimed to identify the genetic cause in a patient with MVA and a distinct, milder phenotype. Methods: We conducted comprehensive clinical and cytogenetic assessments, chromosomal karyotyping, and trio-based exome sequencing on a proband with hypospadias and chromosomal instability. Identified variants were validated by Sanger sequencing and assessed for pathogenicity using ACMG/AMP guidelines. Results: Cytogenetic analysis revealed near-tetraploidy (9.7%) and MVA (46.9%). Exome sequencing identified novel compound heterozygous SMC5 variants, a nonsense c.2221G>T (p.Glu741Ter) and a missense c.3065A>G (p.Asn1022Ser), both predicted to disrupt SMC5/6 complex function. The proband presented with hypospadias and mild developmental delay but lacked the severe neurological, cardiac, or hematological manifestations typical of Atelis Syndrome. Karyotype analysis showed a distinct pattern of chromosomal abnormalities, including a high frequency of marker chromosomes. Conclusions: This report expands the genotypic and phenotypic spectrum of SMC5-related disorders, confirming its association with MVA/near-tetraploidy and describing a novel attenuated clinical presentation. The findings highlight distinct cytogenetic patterns potentially differentiating DNA repair-defective MVA from other subtypes. Full article

Background/Objectives: Acute pulmonary edema (APE) has emerged as an overlooked but life-threatening manifestation of COVID-19, reflecting the intersection of inflammatory, endothelial, and cardiac injury pathways. This study aimed to determine the incidence, independent predictors, and long-term pulmonary sequelae of APE in hospitalized COVID-19 patients. Materials and Methods: We conducted a retrospective cohort study including 127 consecutively admitted adults with confirmed SARS-CoV-2 infection at a tertiary-care center in Romania. Demographic, clinical, biochemical, and imaging data were analyzed. Multivariate logistic regression identified independent predictors of APE and in-hospital mortality, while three-month follow-up assessed pulmonary recovery and biomarker dynamics. Results: APE occurred in 36.2% of patients and was associated with a four-fold increase in in-hospital mortality (43.5% vs. 12.3%, p < 0.001). Elevated NT-proBNP, troponin I, and IL-6 levels independently predicted both APE occurrence and mortality. APE patients required more frequent ICU admission (52.2% vs. 18.5%, p < 0.001) and had longer hospital stays. At three months, 39% of APE survivors exhibited fibrotic CT changes, and 37% had restrictive ventilatory defects, correlating with persistently increased NT-proBNP and IL-6 concentrations. Conclusions: Acute pulmonary edema delineates a distinct cardio-inflammatory phenotype of COVID-19, driven by endothelial dysfunction and biomarker-elevated cardiac stress. Early biomarker-guided fluid management and structured multidisciplinary follow-up may mitigate both acute mortality and chronic pulmonary sequelae in post-COVID populations. Full article

Myotonic Dystrophy Type 1 (DM1) is a complex multisystemic genetic disorder caused by CTG repeat expansions in the DMPK gene, leading to RNA toxicity and widespread splicing defects. These splicing abnormalities affect multiple systems, including the respiratory, skeletal, cardiac, nervous, and endocrine systems, resulting in aggressive symptoms that significantly impact quality of life and survival. Cardiac complications are the second leading cause of deaths in DM1, after respiratory insufficiency. Current research is largely focused on understanding cardiac pathology in DM1. This review highlights recent advancements in the clinical and pathological characterization of DM1 cardiac involvement, preclinical models used to study cardiac dysfunction, and emerging therapeutic strategies that target the molecular basis of DM1. Promising approaches include RNA-targeting strategies such as antisense oligonucleotides (ASOs), gene-editing tools like CRISPR-Cas9, and small molecules that modulate RNA splicing. ASOs aim to reduce toxic RNA accumulation, CRISPR-based approaches aim to excise or correct the expanded CTG repeats, and repurposed small-molecule drugs, such as vorinostat, tideglusib, and metformin, could serve as potential therapeutic agents for DM1 patients with cardiac complications. Despite this progress, several challenges remain: the heterogeneity of cardiac manifestations, unpredictable and often silent progression of arrhythmias, limited therapeutic options beyond implantable cardioverter-defibrillator (ICD)/pacemaker implantations, and complex interplay with the multisystemic nature of DM1. More research and well-designed clinical trials are urgently needed to translate these promising strategies into effective treatments for DM1-associated cardiac disease. Here, we discuss the current knowledge in DM1 cardiac pathology and preclinical models as well as the benefits and pitfalls of the available therapeutic approaches. Full article

Background: Cardiac amyloidosis is more common than previously thought with an incidence of up to 15% in aortic stenosis and heart failure with preserved ejection fraction. Pacemaker need in these patients ranges from 9.5% to 20%; however, its prevalence and clinical relevance in patients with unexplained cardiac conduction defects remain unclear. Methods: This retrospective, single-center cohort study evaluated 1107 patients who underwent intracardiac device implantation for unexplained cardiac conduction defects between 2015 and 2024. Patients with secondary conduction defects or known cardiomyopathy were excluded. The prognostic value of the T-AMYLO score and associated red flag findings were assessed in relation to the composite primary endpoint: all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke. Results: Over a median of 58 months for follow-up, 460 patients experienced a primary event, including 346 deaths. Higher event rates were observed in older males, those with atrioventricular block, and patients receiving single-lead ventricular devices. T-AMYLO score and the presence of red flag findings, particularly aortic valve disease, AV block, peripheral neuropathy, low voltages and increased septal thickness were significantly associated with adverse outcomes. Multivariate Cox regression identified elevated T-AMYLO score (HR: 1.06, p = 0.012), aortic valve disease (HR: 1.29, p = 0.016), and AV block (HR: 1.43, p = 0.009) as independent predictors of mortality. Survival analyses confirmed a stepwise decline in prognosis with an increasing T-AMYLO risk group and red flag burden (p < 0.001). Conclusion: These findings highlight the importance of incorporating T-AMYLO scoring and red flags assessment in patients with conduction defects to improve early detection of cardiac amyloidosis and guide risk stratification for outcomes. Full article

2-(Methylthio) benzothiazole (MTBT) is widely used in the industrial and pharmaceutical fields, but limited research has been conducted on its aquatic toxicity. In this study, we established a zebrafish model to systematically evaluate its developmental and functional toxicity, focusing on the cardiovascular systems of larvae. The results showed that MTBT significantly reduced heart rate, caused pericardial edema and deformity, delayed cardiac maturation, decreased stroke volume and cardiac output, and led to vascular structural defects. Mechanistically, MTBT upregulated the expression of the core target PTGS2, activated the apoptotic pathway, and mediated cardiovascular toxicity. This study is the first to systematically confirm the cardiovascular toxicity of MTBT, supplementing its toxicological database and providing a scientific basis for the establishment of environmental safety thresholds and risk management. Full article

An atrial septal defect (ASD) is the most common congenital heart defect (CHD) diagnosed in adulthood. It is characterized by significant anatomical heterogeneity and complications that evolve over time. While often asymptomatic in children, the signs of adverse effects of ASD increase with age, including a greater risk of heart failure, stroke, atrial fibrillation (AF), and reduced life expectancy. ASD is traditionally considered a right-heart lesion due to long-term complications such as arrhythmias, right-sided heart failure, thromboembolism, and, in a subset of patients, pulmonary arterial hypertension (PAH). The pathophysiology of atrial shunts also affects the left heart due to volume overload and adverse ventriculo-ventricular interaction. Early diagnosis of interatrial septal anomalies is essential to prevent hemodynamic consequences and/or thromboembolic events. Electrocardiographic (ECG) findings play a crucial role in this early diagnosis. This narrative review aims to update clinicians on the latest evidence regarding the pathophysiological link between ASD and cardiac rhythm disorders, the nuances of optimal diagnostics, treatment options (surgical, interventional, pharmacological), and the need for long-term follow-up for patients with ASD. The review will determine the risk of conduction disorders compared to a healthy population and to compare the prevalences of conduction disorders, mortality, and pacemaker use in patients with closed ASDs versus those with open ASDs. Full article

Arrhythmias significantly contribute to morbidity and mortality in patients with congenital heart disease (CHD). While postoperative factors predisposing to arrhythmias are well-established, early electrophysiological alterations in pediatric CHD remain poorly understood. This review summarizes current knowledge on postnatal cardiac maturation, conduction-system development, and electrophysiological abnormalities in pediatric patients with and without CHD. Importantly, arrhythmia prevalence, mechanisms, and clinical relevance are systematically discussed across three pediatric groups, including healthy children and patients with unrepaired and repaired CHD. Understanding developmental arrhythmogenic mechanisms may facilitate early risk stratification, guide clinical management decisions, and improve long-term outcomes for pediatric patients with CHD. This review discusses the complex interplay between cardiac maturation, congenital defects, and arrhythmogenesis. It also outlines future directions that include noninvasive monitoring, selective intraoperative mapping, animal model studies, and standardized data collection to improve early risk stratification and long-term outcomes in children with CHD. Full article

Background/Objectives: This study aimed to investigate the prevalence of liver damage and its associated non-invasive markers and echocardiographic risk factors in patients who underwent surgery for congenital heart disease. Methods: This retrospective observational study was conducted at a single tertiary-care university hospital in Niigata, Japan. Of 142 patients (ventricular septal defect [VSD] n = 47, tetralogy of Fallot [TOF] n = 67, Fontan n = 28), 52.8% were male [median age: 22.7 years; VSD (24.3 years), TOF (24.0 years), and Fontan (12.5 years)]. Pediatric patients with liver diseases unrelated to congestive liver disease, such as viral hepatitis and alcoholic liver disease, were excluded. We compared non-invasive liver fibrosis age-invariant biomarkers, such as the aspartate aminotransferase-to-platelet ratio index (APRI), and various serum markers and echocardiographic parameters to assess the prevalence and predictors of hepatic fibrosis. Results: The Fontan circulation group had the highest APRI, followed by the TOF group, while the VSD group had a low risk of APRI elevation. Postoperative TOF patients required monitoring for cirrhosis progression. Inferior vena cava mobility was associated with echocardiographic parameters and fibrosis severity, along with a loss of respiratory variability. The limitations of other cardiac assessments were highlighted by poor anatomical measurements. Gamma-glutamyl transpeptidase (γ-GTP) demonstrated strong discriminatory ability. The optimal cutoff value was 53.0 U/L, suggesting its use as a clinical marker. Conclusions: Assessing fibrosis is crucial in CHD patients, especially those with late post-TOF repair findings. Non-invasive markers (APRI, γ-GTP, and B-type natriuretic peptide), along with echocardiographic findings, may help detect fibrosis early, enabling timely intervention and improving long-term outcomes. Clinical trial registration: 2020-0199. Full article

Background: Acute SARS-CoV-2 infection may induce cardiac arrhythmias associated with viral myocarditis, which typically disappear in the convalescent phase after healing of the myocardial inflammation. Methods: We report the case of a 37-year-old woman with a childhood history of atrial septal defect repair and stable normofrequent atrial rhythm, who presented two months post-COVID-19 with palpitations and dizziness. Diagnostic evaluation included cardiac magnetic resonance imaging (CMR), 24 h Holter electrocardiogram (ECG) monitoring, and laboratory assessments over a 3-year period. Results: CMR suggested subacute myocarditis, and Holter ECG revealed multiple discernible complex cardiac arrhythmias including atrial bradycardia, intermittent junctional rhythm (JR), atrial fibrillation (AF), and non-sustained ventricular tachycardia. Laboratory results showed a moderate but transient increase in lactate dehydrogenase, persistently mildly elevated N-terminal pro–B-type natriuretic peptide (NT-proBNP), and immunoglobulin A (IgA), with all other cardiac, inflammatory, immunologic, and organ function parameters remaining normal. In spite of chaotic cardiac rhythm with alternating JR, AF, and atrial normofrequent rhythm with frequent blocked supraventricular beats and increasing atrioventricular conduction time, no therapeutic intervention was necessary during follow-up, and a conservative treatment approach was agreed with the patient. Two years post-COVID-19 infection, the patient returned to a normofrequent atrial rhythm with a markedly prolonged PQ time (500 ms) and a different P wave morphology compared to pre-COVID, without other rhythm disturbances. Conclusions: This case demonstrates a rare pattern of post-viral arrhythmias first emerging in the convalescent phase and resolving spontaneously after two years. It underscores the need for long-term rhythm surveillance following COVID-19, even in patients with prior structural heart disease and a stable baseline rhythm. Full article

Emery–Dreifuss muscular dystrophy 1 (EDMD1) arises from mutations in EMD. Most EDMD1 patients lack detectable emerin expression. They experience symptoms such as skeletal muscle wasting, joint contractures, and cardiac conduction defects. Currently, physicians rely on treating patient symptoms without addressing the underlying cause—lack of functional emerin protein. Thus, there is a need for therapeutic approaches that restore emerin protein expression to improve patient outcomes. One way would be to deliver emerin mRNA or protein directly to affected tissues to restore tissue homeostasis. Here, we evaluated the utility of lipid nanoparticles (LNPs) to deliver emerin mRNA to diseased cells. LNPs have been studied for decades and have recently been used clinically for vaccination and treatment of a myriad of diseases. Here, we show that the treatment of emerin-null myogenic progenitors with LNPs encapsulating emerin mRNA causes robust emerin protein expression that persists for at least 4 days. The treatment of differentiating emerin-null myogenic progenitors with 2.5 pg/cell emerin LNPs significantly improved their differentiation. The toxicity profiling of emerin mRNA LNP (EMD-LNP) dosing shows little toxicity at the effective dose. These data support the potential use of EMD-LNPs as a viable treatment option and establishes its utility for studying EDMD pathology. Full article

Background: A detailed understanding of cardiac anatomy and physiology is crucial in cardiovascular medicine. However, traditional learning methods often fall short in addressing this complexity. Augmented reality (AR) offers a promising tool to enhance comprehension. To assess its potential integration into the Heidelberger Curriculum Medicinale (HeiCuMed), we conducted a needs assessment among medical students and lecturers at Heidelberg University Medical School. Methods: Our survey aimed to evaluate the perceived benefits of AR-based learning compared to conventional methods and to gather expectations regarding an AR course in cardiovascular medicine. Using LimeSurvey, we developed a questionnaire to assess participants’ prior AR experience, preferred learning methods, and interest in a proposed AR-based, 2 × 90-min in-person course. Results: A total of 101 students and 27 lecturers participated. Support for AR in small-group teaching was strong: 96.3% of students and 90.9% of lecturers saw value in a dedicated AR course. Both groups favored its application in anatomy, cardiac surgery, and internal medicine. Students prioritized congenital heart defects, coronary anomalies, and arrhythmias, while lecturers also emphasized invasive valve interventions. Conclusions: There is significant interest in AR-based teaching in cardiovascular education, suggesting its potential to complement and improve traditional methods in medical curricula. Further studies are needed to assess the potential benefits regarding learning outcomes. Full article

Background/Objectives: Sudden unexpected death in epilepsy (SUDEP) is a major cause of mortality in pediatric epilepsy. Cardiac arrhythmias, possibly reflected by electrocardiographic (ECG) abnormalities, are thought to contribute significantly to SUDEP risk. This study aimed to evaluate ECG indices associated with an increased risk of both atrial and ventricular arrhythmias and sudden cardiac death in pediatric patients with generalized and focal seizures, excluding those with underlying channelopathies. Materials and Methods: Pediatric patients aged 0–18 years with generalized or focal epilepsy followed at our center between October 2024 and April 2025 were enrolled. Comprehensive cardiac evaluations, including echocardiography and 12-lead ECG, were conducted. Patients with channelopathies, structural heart defects, or significant congenital heart disease were excluded. ECG parameters—QT dispersion (QT Disp), corrected QT interval (QTc), QTc dispersion (QTc Disp), P-wave dispersion (P Disp), and T peak-T end interval (Tp-e)—were analyzed across epilepsy subgroups and compared to healthy controls. Effects of antiepileptic drug (AED) use and gender were also assessed. Results: A total of 151 participants were included (generalized: n = 51; focal: n = 50; controls: n = 50). QTc and Tp-e intervals were prolonged in both epilepsy groups compared to controls (p = 0.001 and p = 0.036, respectively), however, they fell within the conventional parameters. AED use was associated with further prolongation of QTc (p = 0.035) and Tp-e (p = 0.037), these metrics were similarly found to be within the established normative boundaries. Phenobarbital and lamotrigine users showed the longest QTc, albeit not statistically significant. Males with generalized seizures had longer maximum P-wave duration (P Max) than females (p = 0.009). A moderate correlation was found between Tp-e and QTc (r = 0.557, p = 0.001). Conclusions: Although there are findings in our study that may suggest a relationship between SUDEP and arrhythmia according to electrocardiographic markers associated with arrhythmia risk, larger and prospective studies with long-term follow-up are needed in the future. Full article