Long QT Syndrome type 2 (LQT2) and Brugada syndrome are inherited cardiac channelopathies that predispose affected individuals to ventricular arrhythmias and sudden cardiac death. We report the case of a 15-year-old male carrying two pathogenic variants: one in SCN5A and one in KCNH2, genes classically associated with Brugada syndrome and LQT2, respectively. The patient presented with an atypical phenotype characterized predominantly by atrial arrhythmias, atrioventricular (AV) conduction abnormalities, and wide complex tachycardia and sinus node disease without the characteristic electrocardiographic features of either syndrome. The phenotype was most likely driven predominantly by the SCN5A variant. Given his unpredictable episodes of high-grade conduction block and potential risk of ventricular arrhythmias, a transvenous implantable cardioverter-defibrillator (ICD) was implanted. Family screening revealed segregation of SCN5A and KCNH2 variants in different relatives, each with mild or absent phenotype. This case highlights the complexity of genotype-phenotype correlations in inherited arrhythmia syndromes and the importance of individualized genetics-informed management.

Hypocalcaemic cardiomyopathy is a rare but potentially reversible cause of heart failure (HF), yet it remains under-recognized in clinical practice. Evidence supporting a direct causal relationship is limited, particularly with regard to relapse and long-term follow-up.

Grayanotoxin poisoning, commonly known as "mad honey" intoxication, is a rare but potentially life- threatening condition primarily affecting the cardiovascular system. It is characterized by bradycardia, hypotension, and, in rare cases, extreme QT interval prolongation, which predisposes patients to malignant arrhythmias. We report a 62-year-old male with no prior cardiac history who developed dizziness, nausea, and cold sweats 30 min after ingesting a tablespoon of mad honey. On admission, he exhibited sinus bradycardia, hypotension (70/40 mmHg), and marked QTc prolongation with giant inverted T waves on electrocardiogram. Laboratory and echocardiographic evaluations were unremarkable. The patient was managed with intravenous hydration and magnesium sulfate, resulting in rapid clinical and electrocardiographic recovery within 24 h. Grayanotoxins exert their toxic effects by modulating voltage-gated sodium channels, leading to sustained depolarization and impaired cardiac conduction. While bradycardia and hypotension are well-documented manifestations, extreme QT prolongation remains a rare but critical complication due to its association with ventricular arrhythmias such as torsades de pointes. This case underscores the importance of vigilant cardiac monitoring and electrolyte management in mad honey poisoning. Early recognition and appropriate supportive treatment can prevent fatal outcomes. Mad honey intoxication should be considered in patients presenting with unexplained bradycardia and hypotension, especially in endemic regions. Extreme QT prolongation, although rare, is a significant electrophysiological disturbance that necessitates prompt intervention to mitigate arrhythmic risk.

Ankyrin-B syndrome, which has been linked to variants in ANK2 and classified as long QT syndrome type 4, is characterised by heterogeneous arrhythmic manifestations, including sinus node dysfunction and conduction abnormalities. Clinically significant atrioventricular block requiring permanent pacing in paediatric patients has rarely been described. We report a 10-year-old boy who presented with recurrent syncope and seizure-like episodes. Electrocardiography demonstrated QT prolongation, and continuous monitoring revealed persistent high-degree atrioventricular block. Genetic testing identified a heterozygous ANK2 variant of uncertain significance (NM_001148.4:c.5626G>A, p. Glu1876Lys), which was also detected in his mother and brother, while his father tested negative. Family evaluation revealed variable phenotypic expression, and a sister who died suddenly at 12 years of age had no available genotype but had autopsy findings of structural cardiac abnormalities. This case highlights clinically significant conduction disease in a child found to harbor an ANK2 VUS and long-QT phenotype and underscores the importance of detailed family phenotyping, rhythm surveillance, and individualised management.

Drug-induced long QT syndrome is a modifiable cause of fatal ventricular arrhythmias. Common drugs such as antiarrhythmics, psychotropic drugs, and antibiotics prolong the QTc interval via potassium channel (hERG/IKr) inhibition and promote torsade de pointes tachycardias. A prerequisite for the diagnosis is an accurate QTc measurement, which is associated with high error rates in automated analysis. In case of suspicion, manual QT measurement is advised, followed by the use of an appropriate formula for heart rate correction. Differential diagnosis should consider congenital long QT syndrome, electrolyte disturbances, intoxication, and structural heart disease, with diagnosis based on the modified Schwartz score. For medication lists and new therapies, drug lists and interaction analyses should be used, particularly to identify high-risk drug interactions such as psychotropic drugs combined with antibiotics and/or diuretics. In cases of increased risk at a QTc interval ≥ 500 ms, trigger substances must be immediately discontinued, and electrolyte, heart rate, and volume status normalized. In acute situations with torsade de pointes tachycardia, treatment using magnesium, isoproterenol, overdrive stimulation, and (if necessary) defibrillation is indicated. Follow-up electrocardiograms before, during, and (if discontinued due to QT prolongation) after therapy until QT normalization, avoidance of further trigger substances, regular follow-up controls, genetic counseling in the case of suspected congenital long QT syndrome, and comprehensive patient education form the basis of aftercare for this condition.

The initial ICH E14 guidance described the thorough QT/QTc (TQT) study with the purpose of evaluating whether a new drug has effects on the QTc interval. Following its adoption, concentration-QTc (C-QTc) modeling was applied to data from TQT studies, and results were comparable with those based on a "by time point" analysis. In 2014, the IQ-CSRC study demonstrated that a small study in healthy subjects using C-QTc as the primary analysis could detect mild drug-induced QTc prolongation. The study led to the revision of the E14 guidance in 2015, allowing the use of C-QTc modeling to exclude a QTc effect at the threshold of concern, 10 ms. The 2015 revision was the starting point for the use of C-QTc modeling applied to data from first-in-human (FIH) studies with the intent to waive requests for a designated TQT study. The 2022 revision (S7B/E14 Q&A) brought non-clinical studies into the decision process for a "definitive" QT evaluation. In this manuscript, the emergence of C-QTc analysis applied to FIH studies with the intent to waive the TQT study is described, and a survey of FDA labels and reviews of approved drugs since 2015 is shared. The uptake has been modest, with only 30% of approved drugs for which a TQT study would be expected using this approach, while a TQT study has been conducted in ∼70% of development programs. It can be expected that the 2022 S7B/E14 revision will increase the number of programs for which a TQT study can be replaced.

Gitelman syndrome is an inherited renal tubulopathy characterized by hypokalemia and hypomagnesemia, which can increase susceptibility to cardiac arrhythmias. Although ventricular arrhythmias have been reported, ventricular tachycardia (VT) storm triggered by atrial tachyarrhythmia with recurrent implantable cardioverter-defibrillator (ICD) therapies is uncommon. A 68-year-old woman with Gitelman syndrome, chronic kidney disease stage IIIa, long-QT physiology, and sinus bradycardia status post pacemaker implantation with subsequent dual-chamber ICD placement presented after palpitations followed by over 35-40 ICD therapies. Initial laboratory evaluation showed profound hypokalemia (2.2 mmol/L) and hypomagnesemia (1.6 mg/dL). Electrocardiography demonstrated a narrow-complex atrial tachyarrhythmia most consistent with atrial flutter, while device interrogation revealed a rapid atrial tachyarrhythmia preceding ventricular tachyarrhythmic events. The episode was clinically interpreted as atrial flutter degenerating into sustained VT. After intravenous potassium, magnesium, and metoprolol, she converted to an atrial-paced rhythm but subsequently developed transient rebound hyperkalemia necessitating temporizing therapy. Echocardiography showed preserved left ventricular systolic function. This report highlights a trigger-mediated VT storm in the absence of structural left ventricular dysfunction. Key management strategies included strict electrolyte control, avoidance of proarrhythmic triggers, optimization of ICD programming, and consideration of an electrophysiology study with potential ablation.