Search Results (14)

Background: PRKAG2-related disease is an autosomal dominant disorder caused by pathogenic variants in the PRKAG2 gene, leading to glycogen accumulation in cardiomyocytes. It is characterized by left ventricular hypertrophy (LVH), ventricular pre-excitation, and conduction disease. Due to the rarity of the condition and the frequent occurrence of private variants, functional or pathological testing is required for definitive pathogenicity classification. Case Presentation: We describe a 22-year-old male referred for evaluation after experiencing exertional dyspnea and a syncopal episode. Family history revealed sudden cardiac deaths and conduction disease requiring pacemaker implantation. The patient exhibited mild LVH on imaging, conduction abnormalities on electrophysiological study, and a heterozygous PRKAG2 variant (c.1643C>T; p.Ser548Leu), classified as likely pathogenic according to ACMG guidelines. Cascade screening identified the variant in three family members, one of whom exhibited a positive phenotype. Endomyocardial biopsy revealed glycogen accumulation, providing histopathological confirmation of PRKAG2-related disease. Conclusions: This case underscores the importance of integrating genetic, clinical, and histopathological data in variant interpretation. Endomyocardial biopsy can provide definitive evidence to reclassify a PRKAG2 variant as pathogenic, thereby guiding management and family screening. Full article

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disorder characterized by structural and functional myocardial alterations, often accompanied by ventricular arrhythmias (VAs), which may ultimately result in sudden cardiac death (SCD). While mutations in genes coding for desmosomal components are commonly identified in affected individuals, genetic variants involving non-desmosomal proteins have recently been recognized as contributors to the disease’s etiology. In 2008, a mutation in the transmembrane protein 43 (TMEM43) was identified as being responsible for a fully penetrant, sex-related, and severe form of ACM. This review aimed to systematically synthesize the current evidence on the natural history, electrocardiographic, and imaging findings as well as the clinical outcomes of TMEM43 cardiomyopathy. Methods: A systematic search was performed in the PubMed, Scopus, and Web of Science databases, following the PRISMA guidelines, using the terms “TMEM43” AND “cardiomyopathy”. After an initial screening of 144 retrieved articles, 80 were considered relevant. Upon a full-text review and eligibility assessment, 12 studies involving 903 individuals harboring TMEM43 variants were selected for inclusion. Results: Male patients more frequently carried the pathogenic TMEM43 variant (n = 505, 55.9%) and exhibited an earlier arrhythmic onset of the disease (33.2 years old versus 46.2 years old in female patients), supporting the need for earlier implantable cardioverter–defibrillator implantation (30.4 versus 42.2 years old). Palpitations, chest pain, and syncope were the most common presenting symptoms. Baseline electrocardiograms commonly demonstrated poor R wave progression, QRS prolongation, and premature ventricular contractions (PVCs). Arrhythmic events, including malignant VAs and SCD, were early manifestations of the disease, especially in male patients. Frequent PVCs and left ventricular dilation were considered early markers of the disease and were predictive of arrhythmic events. Conversely, heart failure was reported as a late clinical outcome, requiring heart transplantation in a minority of cases (1.5%). Conclusions:TMEM43 cardiomyopathy is a fully penetrant autosomal dominant form of ACM, characterized by a well-defined clinical phenotype that is more severe and presents earlier in male patients. Full article

Background/Objectives: Bradycardia, an uncharacteristically low heart rate below 60 bpm, is a commonly reported adverse drug event (ADE) in individuals administered dexmedetomidine for sedation. Dexmedetomidine is frequently used as a sedative and analgesic for both intubated and non-intubated patients due to its low risk of respiratory depression. The purpose of this study was to further characterize the safety profile of dexmedetomidine using safety reports collected from the FDA Adverse Event Reporting System (FAERS) and transcriptomic data. Methods: Association rule mining was used to both identify additional ADEs that presented concurrently with bradycardia in patients sedated with dexmedetomidine, as well as to characterize potential drug–drug interactions (DDIs). Furthermore, public transcriptomic data were analyzed to identify differentially expressed genes that may elucidate the genetic drivers of elevated bradycardia risk in those administered dexmedetomidine. Results: Bradycardia was the most frequently reported ADE for individuals administered dexmedetomidine. Other cardiovascular-related ADEs commonly associated with bradycardia included syncope (lift = 4.711), loss of consciousness (lift = 3.997), cardiac arrest (lift = 2.850), and hypotension (lift = 2.770). Several possible DDIs were identified, including Lactated Ringer’s solution (lift = 5.441), bupivacaine (lift = 2.984), and risperidone (lift = 2.434), which may elevate bradycardia risk. Finally, eight genes related to cardiac muscle contraction were identified as possible regulators of dexmedetomidine-induced bradycardia, including COX5B, COX6A2, COX8B, MYH7, MYH6, MYL2, UQCRQ, and UQCR11 in mouse cardiac cells. Conclusions: Key clinical takeaways include the co-presentation of multiple cardiovascular ADEs, including cardiac arrest, hypotension, and syncope, alongside dexmedetomidine-associated bradycardia. Furthermore, several possible DDIs with dexmedetomidine were also identified. Full article

Background: This paper will identify the potential genetic causes of multimorbidity associated with autosomal dominant congenital cataract (ADCC). Methods: Whole exome sequencing (WES) was performed on 13 individuals affected with ADCC. Subsequent bioinformatic analyses identified variants with deleterious pathogenicity scores. Results: Disease-causing variants were identified in 8 genes already linked to cataract (CHMP4B, CRYAA, CRYBA1, CRYGD, CYP21A2, GJA8, OPA1, and POMGNT1), but variants previously associated with systemic disorders were also found in a further 11 genes (ACTL9, ALDH18A1, CBS, COL4A3, GALT, LRP5, NOD2, PCK2, POMT2, RSPH4A, and SMO). All variants were identified via pipeline data analysis, prioritising rare coding variants using Kaviar and the Genome Aggregation Database. The following ADCC-associated non-ocular phenotypes were identified in four patients in the cohort: (i) Horner’s pupils, vaso-vagal syncope, and paroxysmal orthostatic tachycardia syndrome; (ii) reduced kidney function and high cholesterol; (iii) hypertension, high cholesterol, and kidney stones; and (iv) grade 1 spondylolysis. Conclusions: We report 11 novel genes identified in an ADCC patient cohort associated with systemic disorders found, along with 8 known cataract-causing genes. Our findings broaden the spectrum of potentially cataract-associated genes and their related lens phenotypes, as well as evidence multimorbidities in four patients, highlighting the importance of careful multisystem phenotyping following genetic analysis. Full article

Neurally mediated syncope (NMS) is associated with a sudden loss of consciousness. However, the diagnostic tools and measures for prognosis management are limited. To overcome these limitations, the differences in the binding energies of Giα-protein-coupled receptors to the Glu9 and Glu12 residues on the α2B-AR gene were elucidated through the analysis of α2B-AR gene polymorphism. The suppression of the activity of adenylate cyclase (AC), which is involved in vasoconstriction, may be related to the onset of NMS. The head-up tilt (HUT) test results indicated differences in systolic blood pressure (SBP) and AC activity between patients with vasodepressor (VT)-NMS and healthy volunteers. Patients with VT-NMS had increased AC activity and decreased SBP. Conversely, in healthy volunteers, no changes in AC activity or SBP were found. These findings suggest that a high SBP and elevated AC activity at rest are likely to cause syncope. A high incidence of cardiovascular events is found in patients with negative HUT test results, highlighting the importance of investigating the cause of syncope in cases where the HUT test results are negative. Overall, our results may provide a means of assessing the risk of NMS development within healthy populations and underscore the importance of subsequent treatments for NMS. Full article

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM cases can be attributed to mutation of the MYBPC3 gene, which encodes cMyBP-C, a crucial structural protein of the cardiac muscle. The manifestation of HCM’s morphological, histological, and clinical symptoms is subject to the complex interplay of various determinants, including genetic mutation and environmental factors. Approximately half of MYBPC3 mutations give rise to truncated protein products, while the remaining mutations cause insertion/deletion, frameshift, or missense mutations of single amino acids. In addition, the onset of HCM may be attributed to disturbances in the protein and transcript quality control systems, namely, the ubiquitin–proteasome system and nonsense-mediated RNA dysfunctions. The aforementioned genetic modifications, which appear to be associated with unfavorable lifelong outcomes and are largely influenced by the type of mutation, exhibit a unique array of clinical manifestations ranging from asymptomatic to arrhythmic syncope and even sudden cardiac death. Although the current understanding of the MYBPC3 mutation does not comprehensively explain the varied phenotypic manifestations witnessed in patients with HCM, patients with pathogenic MYBPC3 mutations can exhibit an array of clinical manifestations ranging from asymptomatic to advanced heart failure and sudden cardiac death, leading to a higher rate of adverse clinical outcomes. This review focuses on MYBPC3 mutation and its characteristics as a prognostic determinant for disease onset and related clinical consequences in HCM. Full article

Sinoatrial node dysfunction can manifest as bradycardia, leading to symptoms of syncope and sudden cardiac death. Electronic pacemakers are the current standard of care but are limited due to a lack of biological chronotropic control, cost of revision surgeries, and risk of lead- and device-related complications. We therefore aimed to develop a biological alternative to electronic devices by using a clinically relevant gene therapy vector to demonstrate conversion of cardiomyocytes into sinoatrial node-like cells in an in vitro context. Neonatal rat ventricular myocytes were transduced with recombinant adeno-associated virus vector 6 encoding either hTBX18 or green fluorescent protein and maintained for 3 weeks. At the endpoint, qPCR, Western blot analysis and immunocytochemistry were used to assess for reprogramming into pacemaker cells. Cell morphology and Arclight action potentials were imaged via confocal microscopy. Compared to GFP, hTBX18-transduced cells showed that hTBX18, HCN4 and Cx45 were upregulated. Cx43 was significantly downregulated, while sarcomeric α-actinin remained unchanged. Cardiomyocytes transduced with hTBX18 acquired the tapering morphology of native pacemaker cells, as compared to the block-like, striated appearance of ventricular cardiomyocytes. Analysis of the action potentials showed phase 4 depolarization and a significant decrease in the APD50 of the hTBX18-transduced cells. We have demonstrated that rAAV-hTBX18 gene transfer to ventricular myocytes results in morphological, molecular, physiological, and functional changes, recapitulating the pacemaker phenotype in an in vitro setting. The generation of these induced pacemaker-like cells using a clinically relevant vector opens new prospects for biological pacemaker development. Full article

Neurally mediated syncope (NMS) is a common clinical problem. The underlying genetic factors of NMS remain controversial. We hypothesized that cardiac syncope-related genes may contribute to NMS in patients with previous frequent syncopal episodes and/or a family history of syncope. A total of 54 consecutive patients diagnosed with NMS were prospectively enrolled between 2013 and 2016. Inclusion criteria were more than five syncopal episodes with a family history of syncope (n = 17) or more than five syncopal episodes with no family history of syncope (n = 37). Ninety-eight cardiac syncope-related genes (channelopathy: 43 genes, cardiomyopathy: 50 genes, primary pulmonary hypertension: 5 genes) were screened by exome sequencing. All identified variants were classified according to the standards and guidelines by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Of the 54 patients, 17 patients (31.5%) had a family history of syncope. Two patients (3.7%) had pathogenic and likely pathogenic variants (PV/LPV) in cardiac syncope-related genes TTN and MYH7. We investigated genetic variation in patients with frequent NMS with a positive family history of syncope in Korea. PV/LPVs in genes related to cardiomyopathy were associated with recurrent NMS in Korean patients. Closer follow-up of these patients might be needed. Full article

Background: The relationship of Holter recordings of repolarization length to outcome in long QT syndrome (LQTS) is unknown. Methods: Holter recordings and initial 12 lead ECG QTc were related to outcome in 101 individuals with LQTS and 28 gene-negative relatives. Mean QTc (mQTc) and mean RTPc (R-wave to peak T-wave, mRTPc) using Bazett correction were measured, analyzing heart rates 40 to 120 bpm. Previously reported upper limit of normal (ULN) were: women and children (<15 years), mQTc 454, mRTPc 318 ms; men mQTc 446 ms, mRTPc 314 ms. Results: Measurements in LQTS patients were greatly prolonged; children and women mean mQTc 482 ms (range 406–558), mRTPc 351 ms (259–443); males > 15 years mQTc 469 ms (407–531), mRTPc 338 ms (288–388). Ten patients had cardiac arrest (CA), and 24 had arrhythmic syncope before or after the Holter. Holter values were more closely related to genotype status and symptoms than 12 lead QTc, e.g., sensitivity/specificity for genotype positive status, mRTPc > ULN (89%/86%); CA, mRTPc > 30 ms over ULN (48%/100%). Of 34 symptomatic (CA/syncope) patients, only 9 (26%) had 12 lead QTc > 500 ms, whereas 33/34 (94%) had an mRTPc or mQTc above ULN. In 10 with CA, all Holter measurements were > 15 ms above ULN, but only two had 12 lead QTc > 500 m. Conclusions: Holter average repolarization length, particularly mRTPc, reflects definite LQTS status and clinical risk better than the initial 12 lead QTc. Values below ULN indicate both a low risk of having LQTS and a low risk of cardiac events in the small percentage that do. Full article

Cardiomyopathies (CMPs) are a heterogeneous group of diseases, frequently genetic, affecting the heart muscle. The symptoms range from asymptomatic to dyspnea, arrhythmias, syncope, and sudden cardiac death. This study is focused on MYH7 (beta-myosin heavy chain), as this gene is commonly mutated in cardiomyopathy patients. Due to the high combined prevalence of MYH7 variants and severe health outcomes, it is one of the most frequently tested genes in clinical settings. We analyzed the clinical presentation and natural history of 48 patients with MYH7-related cardiomyopathy belonging to a cohort from a tertiary center at Helsinki University Hospital, Finland. We made special reference to three age subgroups (0–1, 1–12, and >12 years). Our results characterize a clinically significant MYH7 cohort, emphasizing the high variability of the CMP phenotype depending on age. We observed a subgroup of infants (0–1 years) with MYH7 associated severe DCM phenotype. We further demonstrate that patients under the age of 12 years have a similar symptom burden compared to older patients. Full article

Progressive cardiac conduction disease (PCCD) is a relatively common condition in young and elderly populations, related to rare mutations in several genes, including SCN5A, SCN1B, LMNA and GJA5, TRPM4. Familial cases have also been reported. We describe a family with a large number of individuals necessitating pacemaker implantation, likely due to varying degrees of PCCD. The proband is a 47-year-old-patient, whose younger brother died at 25 years of unexplained sudden cardiac death. Three paternal uncles needed a pacemaker (PM) implantation between 40 and 65 years for unspecified causes. At the age of 42, he was implanted with a PM for two episodes of syncope and the presence of complete atrioventricular block (AVB). NGS analysis revealed the missense variation c. 2351G>A, p.Gly844Asp in the exon 17 of the TRPM4 gene. This gene encodes the TRPM4 channel, a calcium-activated nonselective cation channel of the transient receptor potential melastatin (TRPM) ion channel family. Variations in TRPM4 have been shown to cause an increase in cell surface current density, which results in a gain of gene function. Our report broadens and supports the causative role of TRPM4 gene mutations in PCCD. Genetic screening and identification of the causal mutation are critical for risk stratification and family counselling. Full article

Laboratory medicine, along with genetic investigations in sports medicine, is taking on an increasingly important role in monitoring athletes’ health conditions. Acute or intense exercise can result in metabolic imbalances, muscle injuries or reveal cardiovascular disorders. This study aimed to monitor the health status of a basketball player with an integrated approach, including biochemical and genetic investigations and advanced imaging techniques, to shed light on the causes of recurrent syncope he experienced during exercise. Biochemical analyses showed that the athlete had abnormal iron, ferritin and bilirubin levels. Coronary Computed Tomographic Angiography highlighted the presence of an intramyocardial bridge, suggesting this may be the cause of the observed syncopes. The athlete was excluded from competitive activity. In order to understand if this cardiac malformation could be caused by an inherited genetic condition, both array-CGH and whole exome sequencing were performed. Array-CGH showed two intronic deletions involving MACROD2 and COMMD10 genes, which could be related to a congenital heart defect; whole exome sequencing highlighted the genotype compatible with Gilbert syndrome. However, no clear pathogenic mutations related to the patient’s cardiological phenotype were detected, even after applying machine learning methods. This case report highlights the importance and the need to provide exhaustive personalized diagnostic work up for the athletes in order to cover the cause of their malaise and for safeguarding their health. This multidisciplinary approach can be useful to create ad personam training and treatments, thus avoiding the appearance of diseases and injuries which, if underestimated, can become irreversible disorders and sometimes can result in the death of the athlete. Full article

arrhythmogenic right ventricular dysplasia/cardiomyopathy: an underrecognised disease? Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited myocardial disease that may lead to sudden cardiac death (SCD) and progressive heart failure. Genetic studies have identified causative mutations in genes encoding desmosomal proteins that reduce the stability of the myocardial structure. Thus, ARVD/C is regarded as a genetically determined myocardial dystrophy. The term “right ventricular” is misleading, as in up to 50% of the cases, the left ventricle is also involved and a broader term such as “arrhythmogenic cardiomyopathy” may be preferred. Since the modification of the original 1994 Task Force criteria by W. McKenna and colleagues in 2010, the diagnosis is established according to the “Revised Task Force Criteria”. These include imaging techniques demonstrating functional a nd structural changes of the right ventricle, fibrous replacement of myocardium through biopsy, electrocardiogram depolarisation and repolarisation abnormalities, ventricular arrhythmias and a positive family history including identification of pathogenic genetic mutations. This approach s hall increase sensitivity for early diagnosis without loosing specificity. Several risk factors for SCD such as syncope, certain mutations and young age at manifestation have been identified, although risk stratification still needs improvement, especially in oligosymptomatic patients. Therapeutic strategies include restriction from strenuous physical exercise, antiarrhythmic drugs such as betablockers, sotalol and amiodarone and implantable cardioverter defibrillators. Life-long follow-up is warranted in asymptomatic carriers of pathogenic mutations due to differences in age-related penetrance. Given the clinical relevance of this underrecognised disease, we have established a research and clinical program with focus on ARVD/C at the Clinic for Cardiology of the University Hospital Zurich. Full article

The congenital long QT syndrome (LQTS) is a monogenic disorder, not as rare as it was originally estimated to be, mainly caused by mutations in genes encoding for ion channels. Molecular screening in this disease is part of the diagnostic process and this has already been recognized by current guidelines since 2006. However, very recently, two consensus documents have been published, with the recommendations for the use of genetic testing in the clinical evaluation of genetically transmitted arrhythmogenic diseases. Therefore, we devoted a specific section of the present review to the discussion of these two documents in relation to LQTS. The clinical presentation of the disease is typically characterized by a prolongation of the QT interval on the electrocardiogram (ECG) and by the occurrence of syncope or cardiac arrest, mainly precipitated by sympathetic activation. While the diagnosis of typical cases it is quite easy, borderline cases can be quite challenging and therefore the availability of diagnostic criteria is very useful to support the diagnostic process. Very recently, the LQTS diagnostic criteria have been updated and they are presented in the current review. Finally, the clinical management of LQTS patients is presented together with a schematic flow-chart and recent data coming from the LQTS-ICD European registry are illustrated. The last part of the review is dedicated at future perspectives and latest results on modifier genes and stem cells are presented. Full article