Home / Deep Research / Familial Long QT Syndrome

Familial Long QT Syndrome

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Long QT Syndrome. Core disease mechanisms, molecular and cellular pathways...

2026-04-21
Asta MONDO:0019171 Model: Asta Scientific Corpus Retrieval 18 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Long QT Syndrome. Core disease mechanisms, molecular and cellular pathways...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 18
  • Snippets retrieved: 20

Relevant Papers

[1] Joint effects of CD8A and ICOS in Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS)

  • Authors: Ling-bing Meng, Yongchao Li, Tingting Lv, Changhua Lv, Lianfeng Liu et al.
  • Year: 2024
  • Venue: Journal of Cardiothoracic Surgery
  • URL: https://www.semanticscholar.org/paper/5a96336f0cee51c440d5c99c8c28b51bb987a8a5
  • DOI: 10.1186/s13019-024-02804-w
  • PMID: 38845009
  • PMCID: 11155187
  • Summary: The identification of shared key genes between LQTS and BWS provides insights into common molecular mechanisms underlying these disorders, potentially facilitating the development of targeted therapeutic strategies.
  • Evidence snippets:
  • Snippet 1 (score: 0.495) > Furthermore, recent research has highlighted the intricate interplay between ion channels and growth-related pathways in cellular physiology.For instance, ion channels play crucial roles not only in cardiac electrophysiology but also in cellular proliferation, migration, and differentiation [10].Conversely, dysregulation of growthrelated pathways can influence ion channel expression and function, thereby impacting cardiac excitability and arrhythmia susceptibility [11].These findings underscore the potential convergence of molecular pathways implicated in LQTS and BWS pathogenesis.Common themes such as genetic factors, chromosomal anomalies, and gene dysregulation may underlie the clinical heterogeneity observed in these syndromes.However, further research is warranted to elucidate the precise molecular mechanisms linking LQTS and BWS and to explore potential therapeutic targets shared between these conditions. > Bioinformatics is an interdisciplinary field that combines computer science with biology, playing a pivotal role in biological research.Significant progress has also been made in protein mass spectrometry analysis, structure prediction, and functional annotation, aiding researchers in understanding protein structure and function [12].With the ongoing technological developments, the role of bioinformatics in fields such as biology, medicine, and drug development will continue to expand [13]. > Recent studies have utilized bioinformatics to explore CD8A as an immune cell infiltration and effective diagnostic biomarker in rheumatoid arthritis [14].Li [15] analyzed ICOS + Tregs as a functional subset of Tregs in immune diseases.Furthermore, recent investigations have begun to explore Long QT Syndrome and Beckwith-Wiedemann Syndrome using bioinformatics techniques [16], including artificial intelligence.Variations in genes and molecular mechanisms exist across different diseases, and the relationship between CD8A, ICOS, Long QT Syndrome, and Beckwith-Wiedemann Syndrome remains elusive. > This study seeks to utilize bioinformatics methods to identify key genes shared among Long QT Syndrome, Beckwith-Wiedemann Syndrome, and normal samples.The research will involve conducting enrichment and pathway analyses.

[2] Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

  • Authors: T. Nakajima, S. Tamura, M. Kurabayashi, Y. Kaneko
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/3d299f57f344d42eff9d3565d1581dae7fb87a54
  • DOI: 10.3390/ijms22083930
  • PMID: 33920294
  • PMCID: 8069124
  • Citations: 6
  • Influential citations: 1
  • Summary: Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy.
  • Evidence snippets:
  • Snippet 1 (score: 0.483) > Recent advances in molecular genetics have identified many causal genes for inherited arrhythmia syndromes (IASs) such as long QT syndrome (LQTS) [1], short QT syndrome (SQTS) [2], Brugada syndrome (BrS) [3,4] and early repolarization (ER) syndrome (ERS) [3,5]. Most causal genes for IASs encode cardiac ion channels or their related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and experimental animal models, have revealed the pathophysiology of IASs and enabled the establishment of causal gene-specific precision medicine [6][7][8]. Furthermore, analyses of patient-specific and/or genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies for IASs, although there are still some limitations of using iPSC-CMs, such as immature structure and function and mixed population of atrial, ventricular, and nodal cells, as a standard technology [9]. > The altered function of causal genes that encode cardiac ion channels is caused by multiple mechanisms, including trafficking defects, producing non-functional channels, altered channel gating properties, and a combination thereof. These altered functions of mutant channels underly the clinical phenotypes of IASs [10][11][12]. Particularly, unique electrophysiological properties of mutant channels have been shown to be associated with the atypical clinical phenotypes of IASs [10,13]. Furthermore, the elucidation of the mechanisms underlying the atypical clinical phenotypes of IASs has raised the possibility of mutation-specific precision medicine. > We herein review the current knowledge of genotype-phenotype relationships, underlying molecular and cellular mechanisms, and established pharmacological therapies of IASs, including LQTS, SQTS, and J wave syndrome (BrS and ERS).

[3] Transcriptome and open chromatin analysis reveals the process of myocardial cell development and key pathogenic target proteins in Long QT syndrome type 7

  • Authors: Peipei Chen, J. Long, Tianrui Hua, Zhifa Zheng, Ying Xiao et al.
  • Year: 2024
  • Venue: Journal of Translational Medicine
  • URL: https://www.semanticscholar.org/paper/0aca10800c23f1c939942b4f6bf992317eb1be09
  • DOI: 10.1186/s12967-024-05125-7
  • PMID: 38528561
  • PMCID: 10964537
  • Citations: 1
  • Summary: TFs and target proteins related to electrophysiology and developmental pathogenicity in ATS myocardial cells are uncovered, obtaining novel targets for potential therapeutic candidate development that does not rely on gene editing.
  • Evidence snippets:
  • Snippet 1 (score: 0.465) > Long QT syndrome type 7 (Andersen–Tawil syndrome, ATS), which is caused by KCNJ2 gene mutation, often leads to ventricular arrhythmia, periodic paralysis and skeletal malformations. The development, differentiation and electrophysiological maturation of cardiomyocytes (CMs) changes promote the pathophysiology of Long QT syndrome type 7(LQT7). We aimed to specifically reproduce the ATS disease phenotype and study the pathogenic mechanism. We established a cardiac cell model derived from human induced pluripotent stem cells (hiPSCs) to the phenotypes and electrophysiological function, and the establishment of a human myocardial cell model that specifically reproduces the symptoms of ATS provides a reliable platform for exploring the mechanism of this disease or potential drugs. The spontaneous pulsation rate of myocardial cells in the mutation group was significantly lower than that in the repair CRISPR group, the action potential duration was prolonged, and the Kir2.1 current of the inward rectifier potassium ion channel was decreased, which is consistent with the clinical symptoms of ATS patients. Only ZNF528, a chromatin-accessible TF related to pathogenicity, was continuously regulated beginning from the cardiac mesodermal precursor cell stage (day 4), and continued to be expressed at low levels, which was identified by WGCNA method and verified with ATAC-seq data in the mutation group. Subsequently, it indicated that seven pathways were downregulated (all p < 0.05) by used single sample Gene Set Enrichment Analysis to evaluate the overall regulation of potassium-related pathways enriched in the transcriptome and proteome of late mature CMs. Among them, the three pathways (GO: 0008076, GO: 1990573 and GO: 0030007) containing the mutated gene KCNJ2 is involved that are related to the whole process by which a potassium ion enters the cell via the inward rectifier potassium channel to exert its effect were inhibited. The other four pathways are related to regulation of the potassium transmembrane pathway and sodium:potassium exchange ATPase (p < 0.05). ZNF528 small interfering (

[4] Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics

  • Authors: C. Terrenoire, Kai Wang, Kelvin W Chan Tung, W. Chung, R. Pass et al.
  • Year: 2013
  • Venue: The Journal of General Physiology
  • URL: https://www.semanticscholar.org/paper/b6d8c7da3c94667fa268fc40848996fa93121757
  • DOI: 10.1085/jgp.201210899
  • PMID: 23277474
  • PMCID: 3536519
  • Citations: 205
  • Influential citations: 15
  • Summary: Understanding the basis for differential responses to drug therapies remains a challenge despite advances in genetics and genomics. Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and to interweave clinical and basic molecular data. We report here the derivation of iPSCs from a long QT syndrome patient with complex genetics. The proband was fou...
  • Evidence snippets:
  • Snippet 1 (score: 0.447) > promise of personalized disease management (Schwartz et al., 1995;An et al., 1996;Moss and Kass, 2005). However, particularly in the case of LQTS, patients with multiple mutations have more severe clinical phenotypes and may respond uniquely to pharmacologic therapies (Westenskow et al., 2004;Itoh et al., 2010;Zhang et al., 2012). In addition, there can be significant clinical variability between individuals with the same LQT mutation, possibly as a result of genetic modifiers. Patient-specific iPSC-CMs represent a platform with potential for investigating the molecular pharmacology of ion channel mutations expressed in these complex genetic backgrounds (Tiscornia et al., 2011;Gnecchi and Schwartz, 2012;Zhang et al., 2012) and may provide unique insight into therapeutic approaches for disease management. > In this study, we report generation of iPSC-CMs from each member of an LQTS-3 (LQT-3) family and the investigation of the molecular pharmacology of key ion channels. The proband had been found to have a Understanding the basis for differential responses to drug therapies remains a challenge despite advances in genetics and genomics. Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and to interweave clinical and basic molecular data. We report here the derivation of iPSCs from a long QT syndrome patient with complex genetics. The proband was found to have a de novo SCN5A LQT-3 mutation (F1473C) and a polymorphism (K897T) in KCNH2, the gene for LQT-2. Analysis of the biophysics and molecular pharmacology of ion channels expressed in cardiomyocytes (CMs) differentiated from these iPSCs (iPSC-CMs) demonstrates a primary LQT-3 (Na + channel) defect responsible for the arrhythmias not influenced by the KCNH2 polymorphism.

[5] The channelopathies: an overview

  • Authors: J. M. Blanckenberg
  • Year: 2002
  • Venue: Southern African Journal of Anaesthesia and Analgesia
  • URL: https://www.semanticscholar.org/paper/b92e98fe413d2274a3c2688ddeb01efb297b1087
  • DOI: 10.1080/22201173.2002.10872953
  • Citations: 1
  • Summary: Because each of these diseases is caused by a discrete abnormality of an ion channel protein, this diverse variety of clinical manifestations is grouped together and described as the channelopathies.
  • Evidence snippets:
  • Snippet 1 (score: 0.445) > What at first glance appears to be a random selection of widely differing clinical presentations and syndromes, has recently been found to have as their common underlying factor an inherited abnormality of the mechanism in the cell wall, the ion channel, which is responsible for the transmembrane passage of various ions. Included in this diverse array of diseases are malignant hyperthermia, long QT syndrome, myotonia congenita, Eaton Lambert syndrome, certain forms of migraine and epilepsy, as well as cystic fibrosis.1 The common pathophysiology in all these diseases is an inherited abnormality of the amino acid sequence of the complex protein structure from which the ion channel is composed. These ion channels are ubiquitous in the body, their expression is not restricted only to excitable cells such as neurons or myocytes, and they may be found in the external membrane as well as internal organelles of cells such as pancreatic and renal cells. Because each of these diseases is caused by a discrete abnormality of an ion channel protein, this diverse variety of clinical manifestations is grouped together and described as the channelopathies.2 In order to better understand the pathophysiology involved in each of the channelopathies, it is necessary to review the normal physiology of the individual ion channels themselves.

[6] Precision medicine for long QT syndrome: patient-specific iPSCs take the lead

  • Authors: Yang Yu, I. Deschênes, Ming-Tao Zhao
  • Year: 2023
  • Venue: Expert Reviews in Molecular Medicine
  • URL: https://www.semanticscholar.org/paper/fa8b7b7f08fdd6c61e5185d1db5559fd0117c060
  • DOI: 10.1017/erm.2022.43
  • PMID: 36597672
  • PMCID: 10302164
  • Citations: 19
  • Summary: The roles of various ion channels in orchestrating APs and molecular aetiologies of various types of Long QT syndrome are described and the usage of patient-specific induced pluripotent stem cell (iPSC) models are highlighted in characterising fundamental mechanisms associated with LQTS.
  • Evidence snippets:
  • Snippet 1 (score: 0.440) > Long QT syndrome (LQTS) is an inherited or acquired arrhythmia syndrome that may co-occur with malignant sudden cardiac death. It is characterised by the prolongation of QT interval and an enhanced threat of ventricular arrhythmia (Refs 1, 2). LQTS is primarily divided into congenital and acquired types. Congenital LQTS is mainly attributed to mutations in ion channels and their accessory proteins. Acquired LQTS is primarily caused by various pharmacological agents (e.g., antibiotics, antidepressants, antihistamines, antineoplastics). > Seventeen genes have been reported to be associated with congenital LQTS. Mutations in three common genes (KCNQ1, KCNH2 and SCN5A) account for more than 75% of clinically validated congenital LQTS cases, whereas less than 5% have been attributed to mutations in other genes (Ref. 3). Genetic aetiologies for the remaining approximately 20% of hereditary LQTS are unknown. Intriguingly, a clinical study revealed that the identical LQTS-relevant mutations are not necessarily linked to the same disease phenotype (Ref. 4). Currently, effective treatment options for LQTS are beta-blockers (propranolol, nadolol, etc.), sodium channel blockers (e.g., mexiletine, flecainide, etc.), and surgical interventions that include left cardiac sympathetic denervation (LCSD) and implantable cardioverter-defibrillator (ICD) (Ref. 5). > In this review, we introduce the clinical manifestations and diagnosis of LQTS. We discuss the molecular basis of ion channels underlying congenital LQTS and explore the potential of modelling LQTS using patient-specific induced pluripotent stem cell (iPSCs). We then summarise the current treatment strategies for LQTS and speculate on the future of precision medicine in LQTS through utilising patient-specific iPSCs and whole-genome sequencing.
  • Snippet 2 (score: 0.439) > Abstract Long QT syndrome (LQTS) is a detrimental arrhythmia syndrome mainly caused by dysregulated expression or aberrant function of ion channels. The major clinical symptoms of ventricular arrhythmia, palpitations and syncope vary among LQTS subtypes. Susceptibility to malignant arrhythmia is a result of delayed repolarisation of the cardiomyocyte action potential (AP). There are 17 distinct subtypes of LQTS linked to 15 autosomal dominant genes with monogenic mutations. However, due to the presence of modifier genes, the identical mutation may result in completely different clinical manifestations in different carriers. In this review, we describe the roles of various ion channels in orchestrating APs and discuss molecular aetiologies of various types of LQTS. We highlight the usage of patient-specific induced pluripotent stem cell (iPSC) models in characterising fundamental mechanisms associated with LQTS. To mitigate the outcomes of LQTS, treatment strategies are initially focused on small molecules targeting ion channel activities. Next-generation treatments will reap the benefits from development of LQTS patient-specific iPSC platform, which is bolstered by the state-of-the-art technologies including whole-genome sequencing, CRISPR genome editing and machine learning. Deep phenotyping and high-throughput drug testing using LQTS patient-specific cardiomyocytes herald the upcoming precision medicine in LQTS.

[7] Long QT syndrome: from genetic basis to treatment

  • Authors: L. Crotti, F. Dagradi, P. Schwartz
  • Year: 2011
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/febdb2efe1958c9d3813665112a3661f30dc4ddf
  • DOI: 10.4081/CARDIOGENETICS.2011.S1.E2
  • Citations: 1
  • Summary: The congenital long QT syndrome is a monogenic disorder, not as rare as it was originally estimated to be, mainly caused by mutations in genes encoding for ion channels, and the availability of diagnostic criteria is very useful to support the diagnostic process.
  • Evidence snippets:
  • Snippet 1 (score: 0.439) > Clinical heterogeneity and variable penetrance among patients with the long QT syndrome sharing the same disease-causing mutation is usually attributed to the coexistence of additional genetic and epigenetic factors that could have a role in modifying the clinical manifestation of the disease. The search for these modifier factors is object of an intense research activity, as they could provide from one side new clinical tools useful for the risk stratification of these patients and from another side they could unveil new mechanisms/pathways involved in arrhythmogenesis, useful for development of novel therapeutic approaches. Some common genetic variants [single nucleotide polymorphisms (SNPs)] in cardiac ion channel genes represented the first good candidates as modifiers of the clinical severity of patients with a disease-causing mutation in these same genes. This hypothesis was proved in 2005, when we investigated a highly symptomatic LQTS proband with a mutation in KCNH2 (A1116V) and her relatives that despite carrying the same mutation were phenotypically mildly affected. 40 The clue of their difference was the coexistence in the proband, but not in the family members, of the common polymorphism KCNH2-K897T (present in 30% of caucasians) in trans with the mutation. 40 eterologous expression studies demonstrated that co-expression of A1116V with K897T exaggerated the I Kr reduction caused by the A1116V mutation, supporting the role of this common polymorphism as a major modifier of the clinical severity in this family. 40 Very recently, in another LQT2 family, the modifying role of K897T was further supported; 41 however, we still do not know whether the effect of the K897T is limited to some KCNH2 mutations or to all LQT2/LQTS patients. > Ideal populations to study the contribution of the so called modifier genes are populations of patients carrying the same disease-causing mutation (i.e. founder populations). 42,43

[8] Gene mutations in cardiac arrhythmias: a review of recent evidence in ion channelopathies

  • Authors: Pi-Yin Hsiao, Hui-Chun Tien, C. Lo, J. Juang, Yihua Wang et al.
  • Year: 2013
  • Venue: The Application of Clinical Genetics
  • URL: https://www.semanticscholar.org/paper/3f16f43ee4137d38eb9d160f7ccbf33870c4d0b6
  • DOI: 10.2147/TACG.S29676
  • PMID: 23837003
  • PMCID: 3699290
  • Citations: 34
  • Influential citations: 1
  • Summary: This review has summarized the significance of unveiling mutations in genes encoding transporter-associated proteins as the cause of congenital LQTS, the technique of catheter ablation applied at the right ventricular outflow tract may be curative for severely symptomatic BrS, and the technology of induced pluripotent stem cells is a promising diagnostic and research tool.
  • Evidence snippets:
  • Snippet 1 (score: 0.433) > Over the past 15 years, molecular genetic studies have linked gene mutations to many inherited arrhythmogenic disorders, in particular, “ion channelopathies”, in which mutations in genes encode functional units of ion channels and/or their transporter-associated proteins in patients without primary cardiac structural abnormalities. These disorders are exemplified by congenital long QT syndrome (LQTS), short QT syndrome, Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Functional and pathophysiological studies have led to better understanding of the clinical spectrum, ion channel structures and cellular electrophysiology involving dynamics of intracellular calcium cycling in many subtypes of these disorders and more importantly, development of potentially more effective pharmacological agents and even curative gene therapy. In this review, we have summarized (1) the significance of unveiling mutations in genes encoding transporter-associated proteins as the cause of congenital LQTS, (2) the technique of catheter ablation applied at the right ventricular outflow tract may be curative for severely symptomatic BrS, (3) mutations with channel function modulated by protein Kinase A-dependent phosphorylation can be the culprit of CPVT mimicry in Andersen-Tawil syndrome (LQT7), (4) ablation of the ion channel anchoring protein may prevent arrhythmogenesis in Timothy syndrome (LQT8), (5) altered intracellular Ca2+ cycling can be the basis of effective targeted pharmacotherapy in CPVT, and (6) the technology of induced pluripotent stem cells is a promising diagnostic and research tool as it has become a new paradigm for pathophysiological study of patient- and disease-specific cells aimed at screening new drugs and eventual clinical application of gene therapy. Lastly, we have discussed (7) genotype-phenotype correlation in relation to risk stratification of patients with congenital LQTS in clinical practice.

[9] The double whammy of ER-retention and dominant-negative effects in numerous autosomal dominant diseases: significance in disease mechanisms and therapy

  • Authors: Nesrin Gariballa, Fedah E. Mohamed, Sally Badawi, Bassam R. Ali
  • Year: 2024
  • Venue: Journal of Biomedical Science
  • URL: https://www.semanticscholar.org/paper/fd94e849860c8fa64b14cdbd8be13351948ff6f4
  • DOI: 10.1186/s12929-024-01054-1
  • PMID: 38937821
  • PMCID: 11210014
  • Citations: 7
  • Summary: The importance of this area of research is emphasized, offering substantial potential for understanding the factors influencing phenotypic variability associated with genetic variants, and current and prospective therapeutic approaches targeted at ameliorating the effects of mutations exhibiting dominant-negative effects are highlighted.
  • Evidence snippets:
  • Snippet 1 (score: 0.432) > It is crucial to highlight that the majority of TGFβ signaling pathways involve dimeric proteins, whether secretory or membrane-bound.As illustrated in a prior review, through an extensive literature search, we have shown that these proteins are implicated in around 25 monogenic human diseases [109].However, the disease mechanisms of these conditions remain underexplored in terms of possible implication of ERQC mechanism and also the potential existence of dominant-negative effects.Further investigation into these aspects is warranted to enhance our understanding of the pathogenesis associated with TGFβ signaling-related monogenic diseases. > Long QT syndromes (LQTS) are a group of autosomal inherited arrhythmogenic disorders characterized by abnormal cardiac activity presented by prolonged QT intervals, leading to a type of arrhythmia known as torsades de pointes [176].Irregularities in the heartbeat have the potential to result in fainting, seizures, or sudden cardiac arrest.LQTS is classified into three primary types based on the causative genes: LQTS1, MIM # 192500, LQST2, MIM # 613688, and LQTS3, MIM # 603830 encoded by the genes (KCNQ1), (KCNH2) and (SCN5A), respectively.These genes encode ion channels essential for cardiac repolarization [177].Nonetheless, each type has distinct triggers, clinical manifestations, severity and penetrance profile, suggesting variable molecular mechanisms involved, in addition to environmental factors, age and gender [178].LQTS2 is associated with KCNH2, a gene that encodes the voltage-gated K + channel α-subunit (Kv11.1),which function as tetrameric complex that consists of four Kv11.1 α-subunit [179]. > Ficker and colleagues reported through immunoprecipitation analysis that Kv11.1 disease-causing variants R752W and G601S show defective trafficking, evidenced by their strong association with molecular chaperones Hsp90 and Hsp70 in the ER.Defective trafficking results in ER-retention of misfolded Kv11.1variants, followed by premature degradation through the ERAD mechanism.

[10] Molecular Mechanisms of Inherited Arrhythmias

  • Authors: C. Wolf, C. Berul
  • Year: 2008
  • Venue: Current Genomics
  • URL: https://www.semanticscholar.org/paper/8dc574fc997d6e863ac851b4a75d122de6d9aa61
  • DOI: 10.2174/138920208784340768
  • PMID: 19440513
  • PMCID: 2679644
  • Citations: 26
  • Influential citations: 3
  • Summary: The molecular basis of inherited arrhythmias in structurally normal and altered hearts is summarized, which helps explain the molecular and functional mechanisms of long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and other electrical myopathies.
  • Evidence snippets:
  • Snippet 1 (score: 0.430) > Inherited arrhythmias can be life threatening, and are major cause of mortality and morbidity in developed nations. Identification of molecular pathways that increase susceptibility to arrhythmia is necessary to prevent disease occurrence, to improve current therapies and to target new drug development. In recent years, the discovery of pathogenic mutations in inherited arrhythmia syndromes has provided novel insights for the understanding and treatment of diseases predisposing to sudden cardiac death. In patients with the long QT syndromes (LQTS), genotype-phenotype relation studies [1] and genetic testing have influenced patient risk stratification [2] and refined treatment strategies [3]. > Arrhythmia mechanisms include abnormal automaticity, triggered activity, and re-entrant excitation. Each of these mechanisms can occur in any type of myocardial disease or in inherited cardiac arrhythmias. The current article focuses on molecular mechanisms of arrhythmias in the structurally abnormal and normal heart. Hypertrophic and dilated cardiomyopathies, as well as arrhythmogenic right ventricular dysplasia/cardiomyopathy are common substrates of inherited arrhythmias in the structurally abnormal heart. Genetic diseases causing arrhythmias in the structural normal heart, also called electrical myopathies, include the long QT syndromes, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), and non-defined familiar idiopathic ventricular fibrillation. Most, but not all of these disorders are caused by mutations in genes encoding cardiac ion-channel proteins. Among family members carrying an identical mutation in a single gene, remarkable phenotypic variability and expressivity may be observed, suggesting both environmental [4] and genetic modifiers [5].

[11] Application of Human Induced Pluripotent Stem Cells for Tissue Engineered Cardiomyocyte Modelling

  • Authors: P. Katili, Amira P. Karima, Winda Azwani, R. Antarianto, M. Djer
  • Year: 2023
  • Venue: Regenerative Engineering and Translational Medicine
  • URL: https://www.semanticscholar.org/paper/230ce81f53920be5341915add9ac3de36432f6f2
  • DOI: 10.1007/s40883-023-00294-1
  • Citations: 5
  • Summary: The cardiac patch is currently the most effective delivery system, proving safety and improvements in animal models, which are suggested to be the role of the paracrine mechanism.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > Disease models of cardiac diseases had been reported for long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), Friedreich's ataxia and Barth syndrome, and syndromic diagnosis associated with cardiomyopathy (LEOPARD syndrome, Pompe disease, laminopathies) [52][53][54][55]. These diagnoses comprise largely of genetic mutations; however, direct causality between genetic and environmental factors that affect disease phenotypes is still largely unknown, and until recently, there has been no reliable, human-sourced model to reenact disease progression outside the human body. hiPSCs allow the collection of diseased cell types to be investigated as cardiomyocytes develop in vitro, enabling the investigation of molecular and cellular mechanisms that contribute to pathological changes in an individual context. > Current studies focus on identifying new genetic mutations and reproducing their phenotypes in vitro using cell lines from diagnosed patients and their families. Disease models of hypertrophic cardiomyopathy (HCM) showed hypertrophy of cardiomyocytes, irregular sarcomere, and interstitial fibrosis in a hiPSC-CMs model. In the study by Lan et al., genetic analysis was carried out on ten patients in 2nd-and 3rd-generation families where one family member had been diagnosed with HCM. A missense mutation confirmed genetic aetiology in the myosin heavy chain (MYH7 gene) in 5 family members, but only one family member showed clinical manifestation [56]. Arrhythmias and irregular calcium handling were also found in the cellular level analysis. Genetic mutations without clinical phenotypes are an exciting area of research, and mechanisms regarding environmental influence on the genetic background are yet to be discovered. To confirm this hypothesis, Tanaka et al. analysed the influence of multiple hypertrophy-promoting factors in the hiPSC-CMs disease model from 3 known HCM patients, in which two of them were negative for known sarcomeric mutations. hiPSC-CMs HCM model treated with endothelin-1 (ET-1) showed disorganised cell hypertrophy and myofibrils compared to negative controls.

[12] Which came first: validity or clinical testing? The example of long QT genes

  • Authors: Lacey J. Boshe, A. K. Foreman, J. Goldstein, Natasha T. Strande, J. Berg et al.
  • Year: 2018
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/3d4e26b266983915b6da5664ffa1d69e8660b724
  • DOI: 10.20517/JTGG.2018.18
  • Summary: Inclusion of the gene on gene-disease associations may help laboratories to determine gene panel content and the ultimate impact of such information on the composition of clinical gene tests as well as their utilization by clinicians and coverage by health insurance policies remains to be seen.
  • Evidence snippets:
  • Snippet 1 (score: 0.422) > OMIM was queried to identify the genes associated with hereditary LQTS and references supporting the association between each gene and LQTS. A comprehensive PubMed query was conducted to identify relevant information for the curation of each gene as described below. PubMed search syntax included the gene symbol and disease name (e.g., LQTS1, "KCNQ1 AND Long QT Syndrome"). > The gene evidence curated from the literature search included: (1) the year each gene was first asserted to be associated with LQTS; (2) the number of clinical cases associated with each gene; (3) the size and number of affected families that exhibit segregation of the phenotype with the genotype; and (4) the robustness of the associated functional data [Table 1]. Cases were included in the total count if the patient had a variant plus either a prolonged QTc on an EKG or clinical symptoms. Segregation data was considered strong if a gene variant was found in the majority of symptomatic or EKG positive members of at least one large family (3 or more generations) without being found in asymptomatic or EKG negative members. Segregation data was considered moderate if the same criteria were met in small families (1 or 2 generations). The robustness of functional data was determined based on the presence of multiple lines of supportive experiments that demonstrated the role for that particular gene in the LQTS disease phenotype. Examples of functional data considered to be supportive of a gene-disease correlation include gene expression analysis that demonstrates the gene is expressed in the target tissue, ion channel protein expression and functional assays, gene knock-out and rescue, animal models and, to a lesser degree, in silico predictions. Genes with numerous and multiple types of functional data were given the highest level of functional evidence. Comparatively, genes with fewer papers/experiments describing functional data from a narrower range of categories were given moderate or minimal levels of functional evidence. Animal models were weighted heavier than the other types of functional data. Gene evidence curation was done initially in November 2014 and last updated in January 2018.

[13] Modelling Human Channelopathies Using Induced Pluripotent Stem Cells: A Comprehensive Review

  • Authors: Martin Müller, T. Seufferlein, A. Illing, J. Homann
  • Year: 2013
  • Venue: Stem Cells International
  • URL: https://www.semanticscholar.org/paper/90202711981d47f844f834f08a2cb7e1d5038224
  • DOI: 10.1155/2013/496501
  • PMID: 23766769
  • PMCID: 3666272
  • Citations: 16
  • Summary: This review summarizes the efforts of reprogramming various types of long QT syndrome and discusses the potential underlying mechanisms and their application.
  • Evidence snippets:
  • Snippet 1 (score: 0.419) > Mutations in long QT syndromes are consistently resulting in a relative increase of depolarizing currents against repolarizing ones (Figure 1). This results in two arrhythmiapromoting situations: (i) channels that remain depolarized for extended periods lead to increased refractory period, thus leading to areas of functional blocking which act as a reentry spot for ectopic excitation; (ii) as the elongation of action potential differs between epicardial (outer) and more endocardial (inner) cardiomyocytes, this may also promote the generation of functional reentry circles [2]. To date, 13 types of long QT syndromes are distinguished. Long QT syndromes are inherited either autosomal dominant or recessive with the recessive ones mostly having a more severe phenotype. Nonetheless, the penetrance in most long QT syndromes differs; as a consequence, there are individuals with mutations without any clinical appearance [4]. > Upon expression of a defined set of transcription factors in somatic cells, iPS cells can be generated from virtually every type of tissue. The first human iPSCs were generated independently in 2007 by the Yamanaka [5] and the Thomson Laboratory [6]. Their unique features of unlimited selfrenewal and nonrestricted differentiation power define a landmark in the context of understanding human development and disease [7][8][9]. More precisely, in case of applying this tool to patients who are classified into a disease group, it enables the generation of disease-specific iPS cells. iPS cells have proven a significant tool to elucidate pathophysiological mechanisms in various diseases such as diabetes, blood disorders, defined neurological disorders, and genetic liver disease [10][11][12]. iPS cells enable the dissection of monogenic human disease [13] mechanisms as well as mechanisms of genetically complex human disorders such as schizophrenia [14]. This opens promising perspectives both for the screening of innovative "druggable" targets [15] and ex vivo gene targeting therapies [13].

[14] Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs

  • Authors: Jeonghyeon Park, K. Noh, H. Lee, M. Lim, S. Seong et al.
  • Year: 2013
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/5230cdd6879c504b17a881b1f292af647e522ccc
  • DOI: 10.1371/journal.pone.0060556
  • PMID: 23593245
  • PMCID: 3617128
  • Citations: 7
  • Influential citations: 1
  • Summary: Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs and would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose.
  • Evidence snippets:
  • Snippet 1 (score: 0.416) > Endogenous metabolites in the human body may change due to many factors, such as dietary habits, the environment, heredity, disease and medicines. We developed a pharmacometabolomic approach to discover metabolic phenotypes that could predict changes in biochemical metabolites directly related to physiological or pathological functions and that can also predict drug toxicity in the guinea pig. Metabolic phenotypes can be applied to understand pharmacological roles related to pharmacodynamics, as well as to pre-clinical or clinical settings. Cardiovascular risk factors are strongly related to abdominal obesity, increased blood pressure, impaired fasting glucose and dyslipidemia, and also increased incidence and lethality of ischemic heart disease and stroke [73,74,75]. Although it is known that such factors increase cardiovascular risk [76,77,78,79], little is known about the relationship with asymptomatic risk factors, such as long QT syndrome on an electrocardiogram. QTc interval prolongation is considered a prognostic factor for arrhythmia although its mechanism has not been completely known, since it is a phenomenon accompanying delayed ventricular repolrarisation [80,81,82,83]. QT interval prolongation is a side effect of sparfloxacin, and has been reported to have I Kr -blocking ability [22,23,24] and to be related to TdP [14]. hERG, one of the genes [84] that can cause long QT syndrome, controls an important repolarising current called I Kr . Guinea pigs have hERG channels and thus are suitable for measuring the proarrhythmic effect [85,86,87]. This integrative approach was applied to predict druginduced QT prolongation of sparfloxacin. Significant prolongation of the QT interval was observed when sparfloxacin was administered at doses of 33.3, 100, and 300 mg/kg [44], and these doses were used in our experiments. We analyzed plasma samples using LC-MS, and detected 1,178 metabolic features.

[15] Modeling Short QT Syndrome Using Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes

  • Authors: I. El-Battrawy, H. Lan, Lukas Cyganek, Zhihan Zhao, Xin Li et al.
  • Year: 2018
  • Venue: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
  • URL: https://www.semanticscholar.org/paper/e917e7f7389eb98708e26a55f784f13735995f9c
  • DOI: 10.1161/JAHA.117.007394
  • PMID: 29574456
  • PMCID: 5907581
  • Citations: 102
  • Influential citations: 6
  • Summary: Patient‐specific hiPSC‐CMs are able to recapitulate single‐cell phenotype features of SQTS and provide novel opportunities to further elucidate the cellular disease mechanism and test drug effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.415) > Background Short QT syndrome (SQTS), a disorder associated with characteristic ECG QT‐segment abbreviation, predisposes affected patients to sudden cardiac death. Despite some progress in assessing the organ‐level pathophysiology and genetic changes of the disorder, the understanding of the human cellular phenotype and discovering of an optimal therapy has lagged because of a lack of appropriate human cellular models of the disorder. The objective of this study was to establish a cellular model of SQTS using human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs). Methods and Results This study recruited 1 patient with short QT syndrome type 1 carrying a mutation (N588K) in KCNH2 as well as 2 healthy control subjects. We generated hiPSCs from their skin fibroblasts, and differentiated hiPSCs into cardiomyocytes (hiPSC‐CMs) for physiological and pharmacological studies. The hiPSC‐CMs from the patient showed increased rapidly activating delayed rectifier potassium channel current (IK r) density and shortened action potential duration compared with healthy control hiPSC‐CMs. Furthermore, they demonstrated abnormal calcium transients and rhythmic activities. Carbachol increased the arrhythmic events in SQTS but not in control cells. Gene and protein expression profiling showed increased KCNH2 expression in SQTS cells. Quinidine but not sotalol or metoprolol prolonged the action potential duration and abolished arrhythmic activity induced by carbachol. Conclusions Patient‐specific hiPSC‐CMs are able to recapitulate single‐cell phenotype features of SQTS and provide novel opportunities to further elucidate the cellular disease mechanism and test drug effects.

[16] MTMR4 SNVs modulate ion channel degradation and clinical severity in congenital long QT syndrome: insights in the mechanism of action of protective modifier genes

  • Authors: Y. Lee, Luca Sala, M. Mura, M. Rocchetti, M. Pedrazzini et al.
  • Year: 2020
  • Venue: Cardiovascular Research
  • URL: https://www.semanticscholar.org/paper/ea0d921c83677ac82cac1ea791c6c3af20f4a804
  • DOI: 10.1093/cvr/cvaa019
  • PMID: 32173736
  • PMCID: 7898949
  • Citations: 38
  • Summary: This finding represents the first demonstration of the cellular mechanism of action of a protective modifier gene in LQTS and provides new clues for advanced risk stratification and paves the way for the design of new therapies targeting this specific molecular pathway.
  • Evidence snippets:
  • Snippet 1 (score: 0.411) > One of the most puzzling questions in arrhythmic disorders of genetic origin concerns why the clinical manifestations in two siblings carrying the same disease-causing mutations may vary from benign to highly malignant. Genetic variants acting as 'modifier genes' are the commonly accepted explanation. 1 The congenital long QT syndrome (LQTS) is caused by mutations of the genes encoding ion channels or excitationcontraction coupling proteins, 2 has a prevalence of 1 in 2000, 3 is associated with life-threatening arrhythmias, 4 shows a good genotype-phenotype correlation, 5 and is regarded as a paradigm for sudden cardiac death. 6 QT1, the most common type of LQTS, is caused by loss-of-function mutations on the KCNQ1 gene encoding for the repolarizing current I Ks. 2,5 As I Ks mutations impair QT shortening during heart rate increase, most arrhythmic events among LQT1 patients are triggered by sympathetic activation during exercise and emotions. 5 ere, we performed cellular electrophysiology in patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) 7,8 and whole-exome sequencing to identify potential mechanisms by which modifier genes may exert their action in LQTS. We focused on the common mutation KCNQ1-Y111C (henceforth, Y111C) characterized by a generally benign phenotype. 9,10 Y111C is associated with channel trafficking defects 11 and accelerated degradation by the proteasome. 12 By studying a family whose members carry the same Y111C mutation but have distinct clinical severity of LQTS, we discovered two protective single-nucleotide variants (SNVs) on the same gene present in the asymptomatic (AS) Y111C carriers and unravelled their mechanism of action.
  • Snippet 2 (score: 0.406) > Abstract Aims In long QT syndrome (LQTS) patients, modifier genes modulate the arrhythmic risk associated with a disease-causing mutation. Their recognition can improve risk stratification and clinical management, but their discovery represents a challenge. We tested whether a cellular-driven approach could help to identify new modifier genes and especially their mechanism of action. Methods and results We generated human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) from two patients carrying the same KCNQ1-Y111C mutation, but presenting opposite clinical phenotypes. We showed that the phenotype of the iPSC-CMs derived from the symptomatic patient is due to impaired trafficking and increased degradation of the mutant KCNQ1 and wild-type human ether-a-go-go-related gene. In the iPSC-CMs of the asymptomatic (AS) patient, the activity of an E3 ubiquitin-protein ligase (Nedd4L) involved in channel protein degradation was reduced and resulted in a decreased arrhythmogenic substrate. Two single-nucleotide variants (SNVs) on the Myotubularin-related protein 4 (MTMR4) gene, an interactor of Nedd4L, were identified by whole-exome sequencing as potential contributors to decreased Nedd4L activity. Correction of these SNVs by CRISPR/Cas9 unmasked the LQTS phenotype in AS cells. Importantly, the same MTMR4 variants were present in 77% of AS Y111C mutation carriers of a separate cohort. Thus, genetically mediated interference with Nedd4L activation seems associated with protective effects. Conclusion Our finding represents the first demonstration of the cellular mechanism of action of a protective modifier gene in LQTS. It provides new clues for advanced risk stratification and paves the way for the design of new therapies targeting this specific molecular pathway.

[17] An overview on cardiac involvement in Inborn Errors of Metabolism: from clinical clues to nutritional management strategies

  • Authors: C. Montanari, V. Tagi, Martina Tosi, Eliana Stucchi, Eleonora Pisano et al.
  • Year: 2025
  • Venue: Frontiers in Cardiovascular Medicine
  • URL: https://www.semanticscholar.org/paper/53edcd65284033a78e81633fbeb8012f21599561
  • DOI: 10.3389/fcvm.2025.1648010
  • PMID: 41425985
  • PMCID: 12711851
  • Summary: This review examines nutritional strategies for managing patients affected by IEMs with cardiac involvement, providing clinicians with research-backed guidance to support cardiological care, since specific nutritional strategies have shown promise in reversing or improving cardiac function in specific IEMs.
  • Evidence snippets:
  • Snippet 1 (score: 0.408) > Approximately 10% to 30% of the known causes of cardiomyopathy in childhood are attributable to IEMs (10, 130,131). In IEMs, cardiac manifestations can be indicative symptoms discovered during regular multisystem screening. While in disorders like MPS, heart manifestations may dominate the clinical presentation, in others, such as PD, they represent the sole clinical manifestation. Four fundamental mechanisms underlie the pathophysiology of cardiac involvement. First, cardiac symptoms can be linked to a reduction in energy production resulting from genetic mutations in proteins involved in energy homeostasis, molecular transport, or cellular organelles. Second, the intracellular accumulation of intermediates or storage substrates within cardiac myocytes can lead to structural and functional damage of the cardiac tissue. Third, the accumulation of intermediate metabolites may exert toxic effects on cardiac and surrounding tissues, for example, by triggering apoptosis in cardiac myocytes. Fourth, altered cellular functions such as signal transduction, depolarization, and cell adhesion, caused by the absence or alteration of glyconjugates, can compromise tissue integrity and cardiac function. It is important to note that pathogenetic mechanisms, summarized in Figure 3, may often overlap, particularly in later stages of the illness progression (33). In this review, we offered a comprehensive description of the cardiovascular diseases primarily associated with various types of IEMs, to guide cardiologists in the differential diagnosis (Figure 4). Moreover, the diagnosis of an underlying metabolic disorder should rely on the recognition of associated signs and symptoms characteristic of each specific disease. > IEMs have a wide phenotypic spectrum and may be characterized by a late onset or mild organ involvement, remaining misdiagnosed. Following the diagnosis of heart complications, the cardiologist should first conduct a detailed investigation of the patient's and family's medical history, including an assessment of consanguinity and/or the presence of rare inherited disorders. The patient's history should include age of onset of each clinically relevant symptom, the presence of associated pathological conditions and/or symptoms (hypoglycemia, myalgia, neurological issues or liver problems) and the result of neonatal screening.

[18] The continuum of personalized cardiovascular medicine: a position paper of the European Society of Cardiology

  • Authors: P. Kirchhof, K. Sipido, M. Cowie, T. Eschenhagen, K. Fox et al.
  • Year: 2014
  • Venue: European Heart Journal
  • URL: https://www.semanticscholar.org/paper/32d5f1334d80db7bf778e662a62b68c7e8d2fdea
  • DOI: 10.1093/eurheartj/ehu312
  • PMID: 25148837
  • PMCID: 4258224
  • Citations: 87
  • Influential citations: 4
  • Summary: Clinical information obtained from history and physical examination, functional and imaging studies, biochemical biomarkers, genetic/epigenetic data, and pathophysiological insights into disease-driving processes need to be integrated into a new taxonomy of CVDs to allow personalized disease management.
  • Evidence snippets:
  • Snippet 1 (score: 0.406) > Several familial, monogenic heart diseases such as hypertrophic cardiomyopathy or the long QT syndromes have been well characterized. The genetic defects have been reported, and disease mechanisms have been described in suitable models. The clinical impact of the underpinning molecular defects on diagnosis, risk stratification, and management remains rather heterogeneous. 55 Despite this progress, mechanism-based or genotype-specific prevention of sudden death has yet to become clinical reality: 56 The long QT syndromes are the only example where the genetic defect can inform prognosis and hence management at present. 56 Only recently some studies have approached the field with a more integrated 'omics' view to investigate the consequences on the phenotype of polymorphisms in the coding regions of causative genes and in other regulatory gene structures as well as the role of gene -gene interaction to regulate protein expression. There is expectation that these investigations will provide insights in the identification of patients at a higher risk of life-threatening arrhythmias. > Pharmacogenomics, i.e. the use of genetic markers to identify patients at risk for adverse reactions to pharmacotherapy, has been proposed for several cardiovascular therapeutics including antithrombotic agents, antiarrhythmic drugs, 2,57 or rhabdomyolysis on statin therapy. 58 Even though the evidence for genetically conferred differences in the response, e.g., to oral anticoagulants is good, controlled trials of genotype-informed dosing did not improve therapy. 59,60 The interaction of ambient and inherited factors that often results in unexpected reactions to therapy may be easier assessed using integrated functional biomarkers, e.g., clinical profiles (as done in warfarin dosing schemes) or ECG changes, 30,61 on therapy.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.