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Timothy syndrome (TS), characterised by multiple system malfunction especially the prolonged corrected QT interval and synchronised appearance of hand/foot syndactyly, is an extremely rare disease affecting early life with devastating arrhythmia. In this work, firstly, the various mutations in causative gene CACNA1C encoding cardiac L-type voltage-gated calcium channel (LTCC), regard with the genetic pathogeny and nomenclature of TS are reviewed. Secondly, the expression profile and function of CACNA1C gene encoding Cav1.2 proteins, and its gain-of-function mutation in TS leading to multiple organ disease phenotypes especially arrhythmia are discussed. More importantly, we focus on the altered molecular mechanism underlying arrhythmia in TS, and discuss about how LTCC malfunction in TS can cause disorganised calcium handling with excessive intracellular calcium and its triggered dysregulated excitation–transcription coupling. In addition, current therapeutics for TS cardiac phenotypes including LTCC blockers, beta-adrenergic blocking agents, sodium channel blocker, multichannel inhibitors and pacemakers are summarised. Eventually, the research strategy using patient-specific induced pluripotent stem cells is recommended as one of the promising future directions for developing therapeutic approaches. This review updates our understanding on the research progress and future avenues to study the genetics and molecular mechanism underlying the pathogenesis of devastating arrhythmia within TS, and provides novel insights for developing therapeutic measures.

PurposeHydroxychloroquine, chloroquine, and azithromycin have been used for treatment of COVID-19, but may cause QT prolongation. Minority populations are disproportionately impacted by COVID-19. This study evaluates the risk of QT prolongation and subsequent outcomes after administration of these medications in largely underrepresented minority COVID-19 patients.MethodsWe conducted an observational study on hospitalized COVID-19 patients in the Montefiore Health System (Bronx, NY). We examined electrocardiograms (ECG) pre/post-medication initiation to evaluate QTc, HR, QRS duration, and presence of other arrhythmias.ResultsOne hundred five patients (mean age 67 years; 44.8% F) were analyzed. The median time from the first dose of any treatment to post-medication ECG was 2 days (IQR: 1–3). QTc in men increased from baseline (440 vs 455 ms, p < 0.001), as well as in women (438 vs 463 ms, p < 0.001). The proportion of patients with QT prolongation increased significantly (14.3% vs 34.3%, p < 0.001) even when adjusted for electrolyte abnormalities. The number of patients whose QTc > 500 ms was significantly increased after treatment (16.2% vs. 4.8%, p < 0.01). Patients with either QTc > 500 ms or an increase of 60 ms had a higher frequency of death (47.6% vs. 22.6%, p = 0.02) with an odds ratio of 3.1 (95% CI: 1.1–8.7). Adjusting for race/ethnicity yielded no significant associations.ConclusionsHydroxychloroquine, chloroquine, and/or azithromycin were associated with QTc prolongation but did not result in fatal arrhythmias. Our findings suggest that any harm is unlikely to outweigh potential benefits of treatment. Careful risk-benefit analyses for individual patients should guide the use of these medications. Randomized control trials are necessary to evaluate their efficacies.

Congenital long QT syndrome (LQTS) is characterised by heart rate corrected QT interval prolongation and life-threatening arrhythmias, leading to syncope and sudden death. Variations in genes encoding for cardiac ion channels, accessory ion channel subunits or proteins modulating the function of the ion channel have been identified as disease-causing mutations in up to 75% of all LQTS cases. Based on the underlying genetic defect, LQTS has been subdivided into different subtypes. Growing insights into the genetic background and pathophysiology of LQTS has led to the identification of genotype–phenotype relationships for the most common genetic subtypes, the recognition of genetic and non-genetic modifiers of phenotype, optimisation of risk stratification algorithms and the discovery of gene-specific therapies in LQTS. Nevertheless, despite these great advancements in the LQTS field, large gaps in knowledge still exist. For example, up to 25% of LQTS cases still remain genotype elusive, which hampers proper identification of family members at risk, and it is still largely unknown what determines the large variability in disease severity, where even within one family an identical mutation causes malignant arrhythmias in some carriers, while in other carriers, the disease is clinically silent. In this review, we summarise the current evidence available on the diagnosis, clinical management and therapeutic strategies in LQTS. We also discuss new scientific developments and areas of research, which are expected to increase our understanding of the complex genetic architecture in genotype-negative patients, lead to improved risk stratification in asymptomatic mutation carriers and more targeted (gene-specific and even mutation-specific) therapies.

Concentration-effect (CE) models applied to early clinical QT data from healthy subjects are described in the latest E14 Q&A document as promising analysis to characterise QTc prolongation. The challenges faced if one attempts to replace a TQT study by thorough ECG assessments in Phase I based on CE models are the assurance to obtain sufficient power and the establishment of a substitute for the positive control to show assay sensitivity providing protection against false negatives. To demonstrate that CE models in small studies can reliably predict the absence of an effect on QTc, we investigated the role of some key design features in the power of the analysis. Specifically, the form of the CE model, inclusion of subjects on placebo, and sparse sampling on the performance and power of this analysis were investigated. In this study, the simulations conducted by subsampling subjects from 3 different TQT studies showed that CE model with a treatment effect can be used to exclude small QTc effects. The number of placebo subjects was also shown to increase the power to detect an inactive drug preventing false positives while an effect can be underestimated if time points around tmax are missed.

A diagnosis of congenital long QT interval syndrome based on history and electrocardiogram was made in a child in the absence of readily available genetic testing. A genotype 3 (LQT3) was suspected after exclusion of other variants as the child was non-responsive to beta-blocker and sodium channel blocker medication. As the child continues to show episodic bradycardia, polymorphic ventricular ectopy, and T-wave alternans, a single-chamber automated implantable cardioverter-defibrillator implantation was done successfully. This report highlights how the diagnosis of LQT3 was arrived at as well as the anesthetic challenges in the management of patients with LQTS.

As the coronavirus disease 19 (COVID-19) global pandemic rages across the globe, the race to prevent and treat this deadly disease has led to the “off-label” repurposing of drugs such as hydroxychloroquine and lopinavir/ritonavir, which have the potential for unwanted QT-interval prolongation and a risk of drug-induced sudden cardiac death. With the possibility that a considerable proportion of the world’s population soon could receive COVID-19 pharmacotherapies with torsadogenic potential for therapy or postexposure prophylaxis, this document serves to help health care professionals mitigate the risk of drug-induced ventricular arrhythmias while minimizing risk of COVID-19 exposure to personnel and conserving the limited supply of personal protective equipment.

Precise measurement of the QT interval is often hampered by difficulty determining the end of the low amplitude T wave. Root mean square electrocardiography (RMS ECG) provides a novel alternative measure of ventricular repolarization. Experimental data have shown that the interval between the RMS ECG QRS and T wave peaks (RTPK) closely reflects the mean ventricular action potential duration while the RMS T wave width (TW) tracks the dispersion of repolarization timing. Here, we tested the precision of RMS ECG to assess ventricular repolarization in humans in the setting of drug-induced and congenital Long QT Syndrome (LQTS). RMS ECG signals were derived from high-resolution 24 hour Holter monitor recordings from 68 subjects after receiving placebo and moxifloxacin and from standard 12 lead ECGs obtained in 97 subjects with LQTS and 97 age- and sex-matched controls. RTPK, QTRMS and RMS TW intervals were automatically measured using custom software and compared to traditional QT measures using lead II. All measures of repolarization were prolonged during moxifloxacin administration and in LQTS subjects, but the variance of RMS intervals was significantly smaller than traditional lead II measurements. TW was prolonged during moxifloxacin and in subjects with LQT-2, but not LQT-1 or LQT-3. These data validate the application of RMS ECG for the detection of drug-induced and congenital LQTS. RMS ECG measurements are more precise than the current standard of care lead II measurements.

A 63-year-old woman presented with fever, cough, and recurrent presyncope following a lower respiratory tract infection. Initial telemetry demonstrated intermittent complete atrioventricular block with ventricular premature complexes. Despite correction of electrolyte abnormalities and withdrawal of QT-prolonging medications (prescribed for cough), she developed repetitive episodes of polymorphic ventricular tachycardia triggered by R-on-T phenomena, requiring electrical cardioversion and suppression with overdrive pacing after magnesium and phenytoin proved ineffective. A nasopharyngeal bio fire panel identified Mycoplasma pneumoniae, prompting initiation of targeted antibiotic therapy along with propranolol. Cardiac magnetic resonance imaging demonstrated myocardial edema with biventricular dysfunction, consistent with acute myocarditis. With clinical stabilization, resolution of infection, and restoration of sinus rhythm following 2 weeks of antibiotic therapy, atrioventricular conduction improved; however, the QTc remained persistently prolonged on serial electrocardiograms. This persistent QT prolongation beyond the acute inflammatory phase prompted genetic testing, which revealed an autosomal dominant loss-of-function mutation in KCNH2, consistent with long QT syndrome type 2. Following further stabilization, a dual-chamber permanent pacemaker was implanted to prevent bradycardia-mediated arrhythmogenic triggers. The patient has remained free of recurrent ventricular arrhythmias at 1-year follow-up. In conclusion, this case illustrates a rare convergence of infectious, structural, and genetic substrates producing a potent arrhythmogenic milieu, in which Mycoplasma myocarditis unmasked an underlying severe long QT syndrome 2 (LQT2) phenotype and precipitated malignant polymorphic ventricular tachycardia.

This case report presents a notable instance of subcutaneous implantable cardioverter defibrillator (S-ICD) implantation in a 9-year-old patient diagnosed with Timothy syndrome (TS), which is a rare condition characterized by mutations in the CACNA1c gene. Conventional therapies often have limited efficacy in managing TS. This case is significant, as it represents the youngest age for S-ICD implantation recorded in mainland China. While the absence of ventricular arrhythmias during hospitalization and follow-up is encouraging, it is not sufficient to conclusively establish the safety and feasibility of this intervention in young TS patients. Further research is needed to evaluate the long-term outcomes and to consider S-ICD as a potential standard treatment option for TS. Additionally, there is a need for a more detailed exploration of the molecular mechanisms underlying gene therapy and personalized interventions.

The aim of this study is to investigate the changes in QT, QTc, and Tp-e intervals and Tp-e/QT ratio on surface electrocardiogram (ECG) signals during anaesthesia induction using propofol or sevoflurane after preoperative cefuroxime infusion. Some 120 cases of gynaecological patients are randomly divided into propofol (P) and sevoflurane (S) groups (n=60). After cefuroxime (1.5 g) was infused in the two groups of patients, propofol target controlled infusion (TCI) was conducted in the P group for 5 min to realise a plasma concentration of 4 μg/ml while patients in the S group inhaled anaesthesia by infusing 1.3 MAC sevoflurane for 6 min. The 12-lead ECGs were separately collected before infusing cefuroxime (T1), after infusing cefuroxime (T2), and after infusing propofol or sevoflurane (T3) to measure QT and Tp-e intervals, calculate QTc and Tp-e/QT, and record MAP and HR. Finally, we demonstrated that QT, QTc, and Tp-e intervals and Tp-e/QT ratio had no change (P > 0.05) after cefuroxime infusion in the two groups of patients compared with that before infusing antibiotics. Moreover, after conducting preoperative cefuroxime infusion, using propofol and sevoflurane had no influence on Tp-e interval, but sevoflurane can significantly prolong QT and QTc intervals (P < 0.05).