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At least 19 recordsLinked to original sources
PubMed2025

The clinical and electrocardiographic phenotype of patients with genotype-negative long QT syndrome.

BACKGROUND: Long QT syndrome (LQTS) is a genetic heart disease that increases the risk of ventricular arrhythmias and sudden cardia arrest. Despite advances in genetic testing, a small subset of patients with LQTS remain genetically elusive. OBJECTIVE: This study aimed to determine the prevalence and clinical characteristics of patients with a phenotype of LQTS but without a genotype. METHODS: This study aimed to identify phenotype-positive, genotype-negative patients with LQTS seen at Mayo Clinic (2000-2024). Retrospective data included demographics, clinical evaluations, electrocardiograms, and genetic results. Diagnosis adhered to established criteria, and genotype-negative LQTS was defined by the absence of pathogenic variants despite clinical presentation. RESULTS: The study included 1829 patients with LQTS. Of these, 1706 (93%) had pathogenic or likely pathogenic variants, and 95 patients (5%) had upgraded clinical variants of uncertain significance, leaving 32 (1.7%) with negative genetic tests. Among the genotype-negative patients, 17 underwent next-generation sequencing, identifying a genetic cause in 6 cases (0.3% of the total). The mean age at diagnosis for the remaining 26 patients was 25 &#xb1; 15 years, with 76% being women and an average initial corrected QT of 498 &#xb1; 41 ms. Fourteen patients (53%) experienced cardiac events prior to diagnosis, and 11 (44%) received an implantable cardioverter-defibrillator. The mean follow-up period was 8 &#xb1; 7 years. CONCLUSION: Genotype-negative LQTS accounted for < 2% of our cohort, highlighting diagnostic and management challenges. Comprehensive clinical evaluation and advanced genetic testing remain essential for accurate diagnosis and care.

Humans↗
PubMed2025

Calmodulin D133H Disrupts Cav1.2 and Kv7.1 Regulation to Prolong Cardiac Action Potentials in Long QT Syndrome.

Calmodulin (CaM) plays a central role in cardiac excitation-contraction coupling by regulating ion channels, including the L-type calcium (Ca2+) channel Cav1.2 and the voltage-gated potassium (K+) channel Kv7.1. 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 Cav1.2, prolonging Ca2+ influx, while also reducing activation of Kv7.1, 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.

Calmodulin↗
PubMed1978

De subitaneis mortibus. XXX. Observations on the pathophysiology of the long QT syndromes with special reference to the neuropathology of the heart.

Eight patients (different families) with syncopal attacks and a long QT interval in the ECG died suddenly. Five heard normally and three were born deaf. At postmortem examination of all eight hearts the single consistent abnormality was focal neuritis and neural degeneration within the sinus node, A-V node, His bundle and ventricular myocardium. Although the etiology of this intracardiac neural disease is uncertain, a chronic viral infection or some noninfectious degenerative process are among the plausible causes discussed. If intracardiac neuritis and neural degeneration prove to be a prevalent finding among other victims dying from the long QT syndromes, further consideration should be given to whether there is any genuine hereditary component in the pathogenesis. Because of the asymmetrical and focal distribution of the cardioneural lesions, the response to present forms of medical or surgical treatment of the lung QT syndromes may vary from benefit to harm. Until more is known of the true etiology of the neural disease, treatment will probably remain empirical in nature and should be conducted with cautious clinical observation.

Adolescent↗
PubMed1978

Left stellectomy in the long QT syndrome.

Recent investigations have reaffirmed the role of autonomic innervation of the heart in the genesis of certain cardiac arrhythmias. The long QT syndrome (LQTS) has been described for years, but only recently has evidence of its link to autonomic imbalance been established. A case of LQTS is presented with intraoperative evidence at the time of left stellectomy of life-threatening arrhythmias triggered by stimulation of this neural body. Removal of the left stellate ganglion normalized the electrocardiographic (ECG) abnormalities and has rendered the patient asymptomatic since surgery. Left stellectomy may become definitive therapy for selected patients with the LQTS.

Adult↗
PubMed1979

Prolonged QT interval and cardiac arrhythmias in two neonates: sudden infant death syndrome in one case.

Two neonates with arrhythmias and the long QT syndrome are described. The arrhythmias were detected in utero and both infants were apparently well after birth. The first infant, although well, had a bradycardia for the first 9 days of life. A normal heart rate was documented at 10 days but a prolonged QT interval was not appreciated on the ECG. He was discharged from hospital but died suddenly and unexpectedly 3 days later. A post-mortem examination failed to find a cause for his death which therefore fell into the category of the sudden infant death syndrome (SIDS). A retrospective analysis of the perinatal electrocardiogram showed a probable junctional rhythm with 2:1 conduction to the ventricle; the QT interval was prolonged at 0.52 seconds (QTC = 0.63). The second infant had a QT interval of 0.52 seconds (QTC = 0.54) and frequent ventricular premature beats on a 24-hour electrocardiogram. She was treated with propranolol and remains well 2 years later. Sudden infant death has often been described in the siblings of children with the long QT syndrome and one other report described a case of SIDS which was said to have had a prolonged QT interval on the perinatal ECG. This report, however, provides unquestionable evidence, in one case, of an association between the long QT syndrome and SIDS.

Arrhythmias, Cardiac↗
PubMed2026

Risk stratification in short QT syndrome: Findings from a pooled analysis.

BACKGROUND: In long QT syndrome, longer QT intervals indicate increased arrhythmic risk, and a rate-corrected QT interval (QTc) of &#x2265;500 ms denotes high risk. Establishing similar associations in short QT syndrome (SQTS) remains elusive. OBJECTIVE: This study aimed to demonstrate that shorter QT intervals denote a higher risk of malignant arrhythmias in SQTS and to define the "high-risk" QTc value in SQTS. METHODS: Pooled analysis of patients treated in our institutions or those reported in the literature revealed 162 patients with SQTS and known symptomatic status; 57 of them (35.2%) had arrhythmic symptoms (sudden death, cardiac arrest, or malignant syncope). RESULTS: There was a significant inverse association between the QTc and arrhythmic symptoms (with a median QTc of 315.0 ms [interquartile range 300.5-338.0] among symptomatic patients vs 330.0 ms [interquartile range 312.5-355.0] among asymptomatic patients; P = .0023). Receiver operator characteristics analysis showed that shorter QTc values were associated with a higher risk (area under the curve 0.64 &#xb1; 0.04; P = .0024). When patients were grouped by QTc range, most of those with a QTc of &#x2264;320 ms had malignant arrhythmic symptoms, whereas the reverse was true for those with a QTc of &#x2265;320 ms. Male patients were overrepresented in the SQTS cohort and more so in the subgroup with malignant symptoms. CONCLUSION: This pooled analysis of patients with SQTS demonstrates that, among patients with congenital SQTS, a shorter QTc is associated with a higher risk of malignant ventricular arrhythmias. A QTc shorter than 320 ms correlates with a higher arrhythmic risk. Men seem to be at higher risk.

Humans↗
PubMed2026

Beyond ion channel dysfunction: Integration of the transcriptome and proteome from patient-specific re-engineered cardiac cells, and population-level QT genome-wide association study reveals broad cellular dysfunction.

BACKGROUND: Congenital long QT syndrome (LQTS) is a cardiac channelopathy with increased risk of cardiac-triggered syncope/seizures, sudden cardiac arrest, and sudden cardiac death. OBJECTIVE: This study aimed to describe the transcriptomic and proteomic profiles in patient-derived inducible pluripotent stem cell-derived cardiomyocyte (iPSC-CM) models of the 3 canonical genotypes of congenital LQTS: LQT1, LQT2, and LQT3 and integrate these omics-level findings with each other and with population/clinical level QT-genome-wide association study (GWAS) data. METHODS: LQT1, LQT2, LQT3 and respective isogenic control iPSC-CMs were cultured, and RNA and protein samples were collected. RNA sequencing and mass spectrometry-enabled proteomic analysis was performed. PrediXcan analysis was performed using QT GWAS summary statistics and transcriptome expression data. Differential gene and protein expression and ingenuity pathway analysis (IPA) was performed comparing each LQT genotype with its respective isogenic control. RESULTS: 1645 differentially expressed genes (DEGs) were identified; 13 were altered in all 3 LQTS genotypes. IPA analysis of DEGs revealed 301 altered pathways; 47 were altered in all LQTS genotypes. Proteomic analysis identified 2561 differentially expressed proteins (DEPs); 30 were altered in all 3 genotypes. IPA analysis of DEPs identified 646 altered pathways. 306 genes/proteins were identified as significantly altered in both the transcriptome and proteome; pathway analysis of these 301 genes identified 201 altered pathways. 7 pathways were altered in all 3 LQTS genotypes in both the transcriptome and proteome. Integration of the population-level PrediXcan results and the cardiomyocyte-derived omics results identified multiple shared pathways. CONCLUSION: Multi-omics analysis of LQTS and integration of omics results with QT GWAS data reveals that primary LQTS-causative ion channel defects precipitate secondary alterations in a wide range of cellular pathways. Our findings suggest more broad molecular level changes throughout the cell. This study lays the foundation for further exploration of broad cellular changes resulting from ion channel disturbances and how they contribute to disease mechanism.

Humans↗
PubMed2025

Clinical and electrophysiological characterization of a SCN5A gain-of-function mutation associated with CPVT-like arrhythmia.

The present study aimed to characterize the SCN5A variant I1333V, found in five families with a history of suspected catecholaminergic polymorphic ventricular tachycardia (CPVT). SCN5A encodes the pore-forming subunit of the cardiac voltage-gated sodium channel NaV1.5. Gain of SCN5A function causes long QT syndrome type 3 (LQT3), but its involvement in CPVT is disputed. Nineteen patients harboring the I1333V variant were identified across five families, commonly presenting with exercise-induced arrhythmia, including polymorphic premature ventricular contractions, ventricular bigeminy, couplets, and ventricular tachycardias. Prolonged QT interval was a less consistent finding, and structural myocardial changes were absent. Human NaV1.5/&#x3b2;1 complexes were expressed in Xenopus laevis oocytes, using RNA combinations to emulate homozygous wild-type, heterozygous and homozygous I1333V-mutant conditions. Cells were studied using the cut-open oocyte Vaseline gap voltage-clamp to evaluate effects of I1333V on NaV1.5 function. NaV1.5(I1333V) channels required less depolarization to activate, classifying this variant as gain-of-function. Fast inactivation was unaffected, and action-potential (AP) clamp showed no significant differences in late Na+ current. A computational model of human ventricular myocyte excitability predicted no effect of I1333V on AP duration; instead, it showed stronger Na+ influx during the AP upstroke, concurrent with elevated Ca2+ import via the sodium&#x2011;calcium exchanger. Finally, NaV1.5(I1333V) channels exhibited a diminished response to cAMP (emulating adrenergic stimulation), which also likely contributes to arrhythmogenesis. In conclusion, I1333V is a gain-of-function variant of SCN5A with a unique set of functional consequences. It is associated with cardiac arrhythmia disease characterized by overlapping CPVT-like and LQT3 features. Our findings support that SCN5A should be considered in genetic screening of suspected CPVT.

NAV1.5 Voltage-Gated Sodium Channel↗
PubMed1977

Sudden infant death syndrome (crib death).

Sudden infant death syndrome (SIDS) is diagnosed by the absence of lethal autopsy findings, or in a resuscitatable, "near miss" form with cyanosis, apnea, and bradycardia. The event is unexpected, although a minor respiratory infection is common, and occurs during sleep, between 1 and 6 months of age. There is growing evidence that the victims have had previous hypoxic episodes. Although suffocation is no longer considered a tenable explanation, other forms of airway obstruction are still postulated by many; the evidence, however, favors hypoxia as the common feature. A lethal arrhythmia had been proposed by several groups, based on inappropriate reflex activity, "pathology" of the conduction system, and the long QT syndrome, but the evidence is against arrhythmia as the primary event in most cases of SIDS. Based on the reversible "near miss," apnea is likely as the primary event in SIDS. Several reflexes have the ability to produce apnea, in addition to the relatively common sleep apnea; the crucial aspect, rather, appears to be thefailure of the immature infant to resume respiration. The possibility exists that the infant, who did not have to breather for 9 months of fetal life, literally is not alarmed and aroused by the persistance of apnea. In human and animal studies, respiratory infections and sleep deprivation have been proved to increase the likelihood and duration of sleep apnea. If primary apnea continues for long (45 seconds or more), a dangerous positive feedback develops into hypoxic apnea. Hhis will persist until circulatory failure occurs, or until gasping occurs. The gasp is a highly effective mechanism at birth, but will occur too late for autoresuscitation after the anerobic capacity of fetal life dimineshes; we believe this capacity lasts for approximately 1 month, accounting for the hiatus of crib death, sparing the first month. The "near-miss" infant, after resuscitation, should be monitored at home, if practical, until 6 months of age. A simple cardiac monitor for bradycardia has definite advantage over an apnea monitor alone.

Airway Obstruction↗
PubMed2026

Genetic Research on Cardiac Channelopathies in African and African-Descent Populations: A Scoping Review.

Cardiac channelopathies are inherited arrhythmias that can lead to sudden cardiac death. Despite Africa's extensive genomic diversity, African and African-descent populations remain underrepresented in genetic research, creating gaps in variant interpretation and clinical care. This scoping review aims to map the extent, range, and nature of genetic research on cardiac channelopathies in these populations and to identify key geographic, thematic, and methodological gaps. Using the Joanna Briggs Institute scoping review methodology and the Population-Concept-Context framework, systematic searches in PubMed, Embase, and Web of Science identified original human studies on cardiac channelopathies with genetic data. Extracted variables included study characteristics, populations, types of channelopathies, and reported genes and variants. Forty-four studies met the inclusion criteria. Most studies originated from the United States and South Africa, while West, Central, and East Africa were largely underrepresented. US Black individuals and South African individuals of continental African or African-descended ancestry (excluding populations of European descent such as Cape Afrikaner people) were the most studied groups, with other continental African groups rarely included. Long QT syndrome was the predominant focus, and SCN5A, KCNQ1, and KCNH2 were the most frequently analyzed genes. Many of the genetic variants discussed remained of uncertain significance due to limited functional validation and the underrepresentation of African genomes in reference databases. Genetic research on cardiac channelopathies in populations of African ancestry is limited, restricting variant interpretation, counseling, and risk prediction. Broader African inclusion, expanded gene screening, and functional studies are essential to improve diagnostics and promote equity in genomic medicine.

Humans↗