Search Results (75)

Background/Objectives: Andersen–Tawil Syndrome (ATS) is an ultra-rare autosomal dominant condition secondary to deleterious variants in KCNJ2 or KCNJ5 in the majority of patients. It is variably characterized by a triad of Long QT Syndrome (LQTS)/ventricular arrhythmias with a prominent U-wave, episodic flaccid muscle weakness/paralysis and skeletal abnormalities. Other clinical features include distinctive facial dysmorphisms, dental anomalies, and mild learning difficulties. Limited data are available regarding the initial presenting sign or symptoms of ATS. Methods: In this study, we include data from 18 patients across eight families. In our cohort, the main clues that led probands to genetic testing were syncope (three families), which was associated with dysmorphic features in one case; LQTS (one family); asymptomatic premature ventricular contractions (PVCs) (three families); and a case incidentally identified during routine cardiac evaluations and due to short stature (one family). Results: Following thorough investigations, a prolonged QT interval was detected in five individuals and prominent U-waves were observed in the majority of the court. Distinctive facial features were consistently present (100%) and can be suggested as a clinical tool for accelerated diagnosis. Skeletal manifestations ranged from 37.5% to 93.7% including short stature, scoliosis and finger defects. Only two patients showed periodic paralysis (PP). Conclusions: Regarding the clinical management of ATS, we underline the importance of the multidisciplinary, personalized, and longitudinal approach, where arrhythmia may not be the leading sign but remains the most potentially critical prognostic factor. Full article

Background: Differentiation therapy is a cornerstone in treating hematologic malignancies, particularly acute myeloid leukemia (AML). Differentiation agents target molecular defects blocking myeloid differentiation. However, rapid differentiation can precipitate a life-threatening complication, differentiation syndrome (DS). DS manifests with fever, pulmonary infiltrates, pleural or pericardial effusions, hypotension, and organ dysfunction, often mimicking sepsis or infection. Early recognition in the emergency department (ED) is critical to mitigate morbidity and mortality. This review aims to provide emergency clinicians with practical strategies for the timely identification and management of DS in patients undergoing differentiation therapy. Discussion: Suspicion for DS should be heightened in patients with acute promyelocytic leukemia (M3 AML) who recently started induction chemotherapy, including all-trans retinoic acid or arsenic trioxide, and in those with non-M3 AML receiving differentiation agents (i.e., isocitrate dehydrogenase inhibitors, menin inhibitors, FMS-like tyrosine kinase 3 inhibitors). Imaging can identify pulmonary infiltrates, effusions, and other cardiopulmonary manifestations. Laboratory workups should include complete blood counts with differentials, serum chemistries, cardiac biomarkers, and sepsis panels to exclude infection. Electrocardiography is advised for patients on QT-prolonging agents. Management emphasizes prompt initiation of high-dose corticosteroids and supportive measures such as blood pressure support, intravascular volume optimization, and oxygen therapy or ventilatory support. Multidisciplinary coordination with oncology, hematology, and critical care teams is important to tailor plans and monitor complications. Conclusions: DS represents a diagnostic challenge in the ED due to its nonspecific presentation and mimicry of infection. A high index of suspicion, combined with targeted imaging, laboratory evaluation, and early corticosteroid therapy, can improve outcomes. Full article

Background: Short QT syndrome (SQTS) is a rare inherited cardiac channelopathy associated with high risk of atrial and ventricular arrhythmias and sudden cardiac death (SCD). Data on its natural history, genotype–phenotype correlations, and risk stratification remain limited. We aimed to evaluate all families with a confirmed diagnosis of SQTS identified at our National Referral Center through a descriptive case series, thereby contributing additional real-world data on this rare condition. Methods: A retrospective review was conducted of all families evaluated for suspected SQTS between 2011 and 2025 at the Inherited Cardiac Diseases Unit. Diagnosis was based on 2022 ESC guidelines (QTc ≤320 ms or ≤360 ms plus supportive features), clinical evaluation, and genetic testing. Families meeting diagnostic criteria were included for detailed phenotypic and genotypic characterization and longitudinal follow-up. Results: Among all patients assessed, two families met the criteria for SQTS. One family with three phenotype-positive individuals was gene-elusive. This family had a history of SCD and the proband presented atrial fibrillation. The second family carried a pathogenic KCNJ2 variant (p.Asp172Asn). However, only the proband fulfilled ECG criteria for SQTS (phenotype-positive) and there was no family history of SCD. No patients were treated with pharmacological therapy for QT prolongation. All affected individuals showed stable QT intervals (none <320 ms) and there were no malignant arrhythmic events during follow-up. Conclusions: These two families illustrate the wide phenotypic spectrum of SQTS and underscore the difficulty of risk stratification in asymptomatic individuals. The rarity of the disease, variable penetrance, and absence of robust prospective data hinder evidence-based management. Systematic registry participation and longitudinal studies are essential to refine risk prediction and therapeutic strategies. Full article

Kv11.1 (hERG1) channels, encoded by KCNH2, mediate the rapid delayed rectifier potassium current (I_Kr) crucial for cardiac repolarization. Disruptions, via mutations or antiarrhythmic drugs like dofetilide cause severe arrhythmogenic disorders, including Long QT Syndrome Type 2 (LQT2), Brugada Syndrome (BrS), and Torsades de Pointes (TdP). While Kv11.1’s role in channelopathies and drug-induced arrhythmias is established, understanding its complex regulation and therapeutic targeting remains a challenge. This review synthesizes the structural, functional, and regulatory aspects of Kv11.1 channels and their clinical implications. Recent studies using iPSC-derived cardiomyocytes highlight regulation by PI3K/Akt, PKC, and PKA signaling via phosphorylation (Ser283, Ser890) and interactions with proteins like 14-3-3. Beyond electrophysiology, Kv11.1 influences pathological hypertrophy and non-cardiac functions including insulin secretion. Pharmacological efforts focus on activators to shorten action potential duration and suppress TdP, and blockers with overdose risks. Mutation heterogeneity, exemplified by trafficking impairment (G785D) in LQT2 and gain-of-function (R397C) in BrS, complicates precision therapy. Clinically, systematic risk stratification using electrocardiographic parameters and genotype-specific approaches enables personalized management. Beta-blockers remain first-line therapy for LQTS2, while rigorous avoidance of QT-prolonging medications and electrolyte monitoring form the cornerstones of preventive care. Advancing Kv11.1-targeted therapies with approaches like CRISPR-Cas9 and pharmacological chaperones (e.g., lumacaftor) holds promise for personalized treatments, ultimately reducing arrhythmic events and sudden cardiac death. Full article

Acute myeloid leukemia (AML) is characterized by differentiation arrest, driving blast proliferation, and abnormal blood formation. While differentiation therapy revolutionized acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), its extension into non-APL AML has been limited until recent targeted agents. This narrative review synthesizes preclinical and clinical evidence into differentiation-inducing therapy, with a focus on IDH1/2, FLT3 and menin inhibitors. Following SANRA guidelines, we searched PubMed (2010–September 2025) for clinical trials and key preclinical studies, with particular attention to the molecular mechanism of differentiation induction, clinical efficacy, and the management of differentiation syndrome (DS). IDH1/2 inhibitors (ivosidenib, enasidenib, olutasidenib) yield overall response rates (ORRs) of 30–94% in AML with DS in 10–19%. Menin inhibitors (revumenib, ziftomenib, enzomenib, bleximenib) achieve ORRs of 33–88% in KMT2A-rearranged or NPM1-mutated AML, with DS in 10–25% and QT prolongation as key toxicities. FLT3 inhibitors (gilteritinib, quizartinib) improve survival in FLT3-mutated AML with DS in 1–5%. Resistance mutations limit durability and combinations enhance efficacy. Differentiation therapy represents a paradigm shift towards non-cytotoxic AML management. Improved recognition of DS and rational combination approaches will be essential to maximize the therapeutic benefit. Future research should address mechanisms of resistance and biomarkers to achieve cures beyond APL. Full article

Background/Objectives: Cardiac arrhythmias are among the leading causes of sudden cardiac death (SCD). Pathogenic variants in potassium channel genes play a key role in inherited arrhythmia syndromes, yet their contribution in Central Asian populations remains poorly characterized. Methods: We performed targeted next-generation sequencing (NGS) using a 96-gene custom Haloplex panel in 79 Kazakhstani patients with clinically diagnosed arrhythmias, including atrioventricular block, sick sinus syndrome, and atrial fibrillation. Detected variants in potassium channel genes were classified according to ACMG guidelines and correlated with clinical phenotypes. Results: A total of 52 variants were identified across 11 potassium channel genes. Two likely pathogenic variants (KCNH2 p.Cys66Gly and p.Arg176Trp) and six variants of uncertain significance (VUS) in KCNQ1, KCNE2, KCNE3, and KCNJ8 were detected. Two novel previously unreported variants were found in KCNE5 and KCND3. Patients harboring pathogenic variants commonly presented with early-onset arrhythmias or a positive family history of cardiovascular disease. Carriers of KCNH2 variants exhibited mild QT prolongation and recurrent syncope. Conclusions: This is the first genetic study of potassium channel gene mutations in Kazakhstani patients with cardiac arrhythmias. The detection of pathogenic and novel variants highlights the clinical utility of integrating genetic testing into diagnostic and management pathways for arrhythmia syndromes. Population-specific genomic data are essential for improving risk stratification, guiding medication safety, and enabling cascade family screening in Central Asia. Full article

Calmodulin (CaM) plays a central role in cardiac excitation–contraction coupling by regulating ion channels, including the L-type calcium (Ca²⁺) channel Ca_v1.2 and the voltage-gated potassium (K⁺) channel K_v7.1. Mutations in CaM are linked to severe arrhythmogenic disorders such as Long QT syndrome (LQTS), yet the molecular mechanisms remain incompletely understood. Here, we investigate the structural and functional consequences of the arrhythmia-associated CaM variant D133H. Biophysical analysis revealed that D133H destabilises Ca²⁺ binding at the C-terminal lobe of CaM, altering its Ca²⁺-dependent conformational changes. Electrophysiological recordings demonstrated that CaM D133H impairs Ca²⁺-dependent inactivation (CDI) of Ca_v1.2, prolonging Ca²⁺ influx, while also reducing activation of K_v7.1, thereby limiting repolarising K⁺ currents. Together, these dual defects converge to prolong action potential duration, providing a mechanistic basis for arrhythmogenesis in LQTS. Our findings establish that CaM D133H perturbs both Ca²⁺ and K⁺ channel regulation, highlighting a shared pathway by which calmodulinopathy mutations disrupt cardiac excitability. Full article

Background: Long QT syndrome (LQTS) is characterized by delayed myocardial repolarization, predisposing to malignant arrhythmias such as torsades de pointes, ventricular fibrillation, and cardiac arrest. Recent reports suggest that acquired LQTS (aLQTS) may represent an early manifestation of hypopituitarism, potentially contributing to its increased cardiovascular mortality, although evidence remains limited to 16 published case reports. Objective: The objective was to investigate the relationship between hypopituitarism and corrected QT (QTc) interval. Methods: We retrospectively analyzed data from 185 patients (121 males) with hypothalamic–pituitary disorders who underwent a 12-lead electrocardiogram between April 2023 and September 2024. Clinical characteristics, hormone replacement therapy, and same-day laboratory parameters (electrolytes, fT3, fT4, IGF-I, testosterone) were recorded. QTc was calculated using Bazett’s formula. Multivariate logistic regression identified predictors of QTc prolongation. Results: Age (OR 1.07–1.09, p = 0.02) was a significant predictor in 5 of 8 models. The presence of expansive lesions other than pituitary adenomas, craniopharyngiomas, and Rathke’s cleft cysts was also associated with QTc prolongation (OR 8.35–17.73, p < 0.05 and p = 0.03). Potassium (OR 0.14–0.17, p = 0.09) and albumin-corrected calcium levels (OR 0.0003, p = 0.06) showed consistent, though borderline, associations. Conclusions: Age and the presence of expansive lesions other than pituitary adenomas, craniopharyngiomas, and Rathke’s cleft cysts are the main predictors of QTc duration in patients with hypothalamic–pituitary disease. Electrolyte imbalances—particularly low potassium and albumin-corrected calcium—may further contribute. The influence of specific pituitary deficiencies remains uncertain, likely due to adequate replacement therapy in most patients. Full article

Herbal medicinal products are increasingly used alongside conventional medicines, raising the risk of potential interactions such as pharmacodynamic drug–herb interactions (PD-DHIs) that can cause serious adverse drug reactions (ADRs). This review aims to present available pharmacological, clinical and pharmacoepidemiological literature regarding potential DHIs associated with serotonin syndrome or cardiac arrhythmias. Furthermore, it assesses the current evidence using the Oxford Centre for Evidence-Based Medicine (CEBM) 2009 framework. Serotonin syndrome most often results from combining serotonergic herbs (e.g., St. John’s wort) with antidepressants like serotonin reuptake inhibitors (SSRIs), as supported by repeated case reports and mechanistic plausibility (CEBM Level 3, Grade C). Other herbs such as black cohosh, ginseng, Syrian rue, turmeric, rhodiola, ashwagandha, and L-tryptophan/5-HTP have been linked to serotonin syndrome when used with SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs), but evidence is limited (Levels 4–5, Grade D). For cardiac arrhythmias, PD-DHIs arise when herbs interact with drugs that alter cardiac electrophysiology—such as QT-prolonging agents, psychotropics, antiarrhythmics or digoxin—thereby amplifying arrhythmogenic risk. Ephedra with sympathomimetics is strongly associated with arrhythmias (Level 2–3, Grade B). Licorice may potentiate digoxin and QT-prolonging drugs via hypokalemia (Level 4, Grade C). Other related PD-DHIs include aconite with antiarrhythmics, bitter orange or caffeine with QT-prolonging psychotropics, yohimbine with cardiovascular agents, and aloe or senna with digoxin. Overall, the evidence for PD-DHIs varies from moderate to weak but large-scale pharmacoepidemiological data is scarce. Future approaches, including artificial intelligence with explainable machine learning and network pharmacology, may integrate mechanistic, clinical, and real-world data to improve early detection or prediction of PD-DHIs. However, several specific challenges must be addressed. Therefore, it is crucial for healthcare providers in both clinical and community settings to increase their awareness of these interactions and ADRs to ensure the safe use of herbal remedies alongside conventional therapies. Full article

Background: Dilated cardiomyopathy (DCM) and long QT syndrome (LQTS) are genetically heterogeneous cardiac disorders that contribute significantly to morbidity and sudden cardiac death. Although they are typically considered distinct entities, co-occurrence within families has been increasingly recognized, complicating diagnosis and genetic counseling. Identifying shared genetic determinants may provide insights into overlapping disease mechanisms. Methods: We investigated a multi-generational family in which several members presented with features of both DCM and LQTS. Exome sequencing was performed to identify potential disease-causing variants, and candidate findings were validated by Sanger sequencing. In silico prediction tools and evolutionary conservation analysis were used to assess the pathogenic potential of the identified variant. Results: We identified a novel heterozygous missense variant in the CRYAB gene, c.368G>A (p.Arg123Gln). This variant is located in a highly conserved region critical for protein function and was consistently predicted to be deleterious across multiple computational algorithms. Segregation analysis demonstrated co-occurrence of the variant with disease phenotypes in affected family members. Clinically, several carriers exhibited overlapping features of both DCM and prolonged QT interval, suggesting a dual cardiac phenotype associated with this mutation. Conclusions: Our findings expand the phenotypic spectrum associated with CRYAB mutations, linking them to a combined presentation of dilated cardiomyopathy and long QT syndrome. This underscores the importance of including CRYAB in comprehensive gene panels for inherited cardiac disorders and highlights the need for integrated clinical and genetic evaluation in families presenting with complex cardiac phenotypes. Full article

Introduction. Adverse drug events (ADEs) are between the third and sixth most common cause of death worldwide. Biosimulation studies performed using real-world data could generate relevant drug safety information without exposing patients to ADEs. Methods. Iclepertin (BI-425809) was virtually added to the actual drug regimens of n = 4,405,063 individuals. Changes in risk level were estimated for drug-induced long QT syndrome and CYP450 drug interactions. The properties used for iclepertin included: dose of 10 mg (oral) once daily; bioavailability (F) = 71%; Cmax of 222 nM; CYP3A4 weak affinity substrate (partial metabolic clearance of ~80%); IC₅₀ for hERG block of 30 μM. Results. A change in total medication risk score (MRS) was observed (6.3 ± 6.6 to 7.2 ± 6.6) following the addition of iclepertin in ~50% (n = 2,138,247) of the studied population. Among individuals with a change in MRS, ~65% had a 2-unit increase (max 11 units). The number of individuals classified in the High/Severe MRS category increased by 0.33%. The addition of iclepertin to individuals receiving CYP3A4 perpetrator drugs produced a greater change in MRS (+1.5) when compared to individuals not exposed to CYP3A4 perpetrators (+0.8). An additional 0.0032% of the population (n = 139) would be at risk of QT prolongation following the intake of iclepertin. Subset analyses performed in individuals with schizophrenia (targeted indication) demonstrated that these individuals had higher MRS values (13.0 ± 10.3) compared to those without schizophrenia (6.2 ± 6.9). However, the addition of iclepertin did not produce a greater increase in MRS in the schizophrenia population vs. the control population. Our pharmacoeconomic model did not account for any beneficial effects of the drug but the model based on MRS changes predicted a USD 91 yearly increase in medical expenditures (emergency department visits and hospitalizations) per individual (USD 3172 to USD 3263) following the addition of iclepertin. A similar increase was observed in the schizophrenia population following iclepertin addition. Conclusions. The increase in MRS associated with the addition of iclepertin to the drug regimen of a large population was minimal and mostly driven by CYP3A4 interactions. Using this model, interactions can be identified a priori, making risk mitigable and preventable without exposing patients to toxicity. Full article

Background and Objectives: Early repolarization (ER), previously considered benign for many years, is now recognized as a substantial risk factor for malignant arrhythmia, coronary artery disease, and mortality. The ER pattern, previously regarded as a benign electrocardiographic characteristic, has lately been demonstrated to have a strong association with malignant arrhythmias, coronary artery disease, and elevated death rates. This study seeks to illustrate the prognostic significance of QT interval (QTc) prolongation on electrocardiograms for acute coronary syndrome and death in emergency cases. Prolongation of QTc duration on electrocardiography in emergency room cases may serve as a possible predictor for acute coronary syndrome and mortality. Materials and Methods: A retrospective study was conducted on 924 patients diagnosed with ER in the emergency department from 2020 to 2023. The QTc durations, serum glucose levels, troponin I levels, and additional auxiliary data of the patients were assessed. The alteration in the aVR derivation, often overlooked and deemed insignificant, was compared with clinical severity in ER cases. Results: The average age of the 924 patients in the study was 48.43 (9.65) years, with 30.7% being female. In the non-cardiac group, the mean age was 51.67 (7.98) years, with 738 females (31.9%). The QTc interval in the patient group was 409.54 (33.46) ms, while in the control group it was 411.57 (27.91) ms (p < 0.001). The one-year death rate was 49 (5.3%) for the ER group and nine (0.9%) for the follow-up group. The most common comorbid condition in both groups was tobacco and/or tobacco product intake. Univariate and multivariate regression analyses conducted for both ER types and mortality indicated that QTc prolongation may serve as a predictive factor (p < 0.001). The sensitivity and specificity of prolonged QTc in predicting acute coronary syndrome and mortality were determined to be 76% at the lowest and 98% at the highest levels in ER cases (p < 0.001). The Kaplan–Meier survival analysis for ER types revealed 321 days for the horizontal type and 363 days for the ascending type. Conclusions: Prolonged QTc duration in early repolarization cases may serve as an independent predictor of acute coronary syndrome and mortality. Full article

Objectives: With the growing importance of mobile technology and artificial intelligence (AI) in healthcare, the development of automated cardiac diagnostic systems has gained strategic significance. This review aims to summarize the current state of knowledge on the use of AI in the analysis of electrocardiographic (ECG) signals obtained from wearable devices, particularly smartwatches, and to outline perspectives for future clinical applications. Methods: A narrative literature review was conducted using PubMed, Web of Science, and Scopus databases. The search focused on combinations of keywords related to AI, ECG, and wearable technologies. After screening and applying inclusion criteria, 152 publications were selected for final analysis. Conclusions: Modern AI algorithms—especially deep neural networks—show promise in detecting arrhythmias, heart failure, prolonged QT syndrome, and other cardiovascular conditions. Smartwatches without ECG sensors, using photoplethysmography (PPG) and machine learning, show potential as supportive tools for preliminary atrial fibrillation (AF) screening at the population level, although further validation in diverse real-world settings is needed. This article explores innovation trends such as genetic data integration, digital twins, federated learning, and local signal processing. Regulatory, technical, and ethical challenges are also discussed, along with the issue of limited clinical evidence. Artificial intelligence enables a significant enhancement of personalized, mobile, and preventive cardiology. Its integration into smartwatch ECG analysis opens a path toward early detection of cardiac disorders and the implementation of population-scale screening approaches. Full article

Background/Objectives: Long QT Syndrome type 2 (LQT2) is a cardiac channelopathy linked to pathogenic variants in the KCNH2 gene, which encodes the Kv11.1 potassium channel, essential for cardiac repolarization. Variants affecting splice sites disrupt potassium ion flow, prolong QT interval, and increase the risk of arrhythmias and sudden cardiac death (SCD). Understanding genotype–phenotype correlations is key, given the variability of clinical manifestations even within families sharing the same variant. We aimed to evaluate new pathogenic variants by analyzing genotype–phenotype correlations in informative families. Methods: Genetic and clinical assessments were performed on index cases and family members carrying KCNH2 pathogenic variants, referred for genetic testing between 2010 and June 2023. The next-generation sequencing (NGS) of 210 cardiovascular-related genes was conducted. Clinical data, including demographic details, family history, arrhythmic events, electrocardiographic parameters, and treatments, were collected. Results: Among 390 patients (152 probands) tested for LQTS, only 2 KCNH2 variants had over 5 carriers. The detailed clinical information of 22 carriers of this KCNH2 p.Ser261fs. has already been reported by our research group. Moreover, we identified 12 carriers of the KCNH2 c.77-2del variant, predicted to disrupt a splice site and not previously reported. Segregation analysis showed its high penetrance, supporting its classification as pathogenic. Conclusions: The newly identified KCNH2 c.77-2del variant is a pathogenic, as strongly supported by the segregation analysis. Our findings underscore the importance of further research into splice site variants to enhance clinical management and genetic counseling for affected families. Full article

Congenital long QT syndrome (LQTS) is a group of heritable conditions that are associated with cardiac repolarization abnormalities characterized by QT prolongation on electrocardiogram and the risk of life-threatening arrhythmias. The prenatal detection of LQTS presents significant challenges for clinicians, and a multidisciplinary approach is required for optimal prenatal and postnatal management. In this comprehensive literature review, we describe strategies for the fetal diagnosis of LQTS with variable initial presentation, genetic testing in suspected fetal LQTS, the utility of fetal magnetocardiography as an additional diagnostic tool, prenatal management, and postnatal treatment. We focus on a multidisciplinary team approach including fetal cardiology, adult and pediatric electrophysiology, neonatology, maternal–fetal medicine, and genetic counselors, all playing vital roles in the comprehensive prenatal management and orchestration of postnatal treatment to optimize neonatal outcomes. Full article