Background: Arrhythmia-risk assessment in congenital long-QT syndrome (LQTS) and drug-induced QT prolongation (diQTP) is primarily based on clinical, genetic, and electrical parameters. Electromechanical window (EMW; aortic-valve closure time minus QT interval) assessment outperformed QTc as a predictor of symptomatic status in LQTS. The relationship between QTc and EMW dynamics, and ventricular tachyarrhythmia (VT) timing in LQTS and diQTP is unknown. Methods: 47 LQTS/-VT, 18 LQTS/+VT (3 LQT1, 5 LQT2, 4 LQT3, 3 LQT7, 3 genotype-negative), nine diQTP/+VT and 26 controls were included. QTc and EMW were obtained from standard 12-lead ECGs and ECG-echocardiograms at two or three time points. +VT patients were included if EMW/QTc assessments were performed within two weeks before or after torsades de pointes, ventricular fibrillation, monomorphic or bidirectional VT. Results: Median age was 42 (27-57) years, and 70% were female. In control subjects, EMW remained stably positive over time. In LQTS/-VT patients, EMW was negative without significant variation. In LQTS/+VT and diQTP/+VT patients, transient accentuations of EMW negativity were observed at the time point closest to VT (2 (1 to 7) days to arrhythmia), regardless of whether measured before or after VT. Temporary EMW negativity accentuation was driven by foreshortening of mechanical systole despite concurrent QT prolongation. EMW recovery after VT was similar for patients with or without beta-blocker therapy. Multiple logistic regression analysis identified EMW negativity and EMW dynamics (ΔEMW) as independent predictors of imminent VT in LQTS. An EMW of -75 ms and ΔEMW of -39 ms were optimal cut-offs to predict emergent arrhythmic deterioration in the LQTS cohort. Conclusion: Temporary accentuation of EMW negativity is a marker of impending VT in LQTS and diQTP patients. EMW negativity ≤ -75 ms and a ΔEMW ≥ -39 ms best differentiated LQTS patients with imminent or very recent VT from those not at acute risk.

The authors have declared no competing interest.

PD was supported by the German Academic Scholarship Foundation and the German Research Foundation (Walter Benjamin Programme, 529532291). AKR was supported by Heidelberg University Medical Faculty's Olympia Morata Grant. MEM was funded by the Career Development Programm - Short Term Fellowship - of Heidelberg University, Faculty of Medicine. MS is supported by the Dutch Cardiovascular Alliance, an initiative with support of the Dutch Heart Foundation, and Stichting Hartedroom for financing the Double Dose program 2020-B005. SH receives personal fees for independent scientific advice on early development in the field of heart failure for AstraZeneca, Ribocure, and CSL Behring, and receives research support from AstraZeneca and CSL Behring; the research leading to these results has received funding from the European Union Commission's Seventh Framework program under grant agreement N° 305507 (HOMAGE). The support of IMI2-CARDIATEAM, from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement N° 821508 is acknowledged; The JU receives support from the European Union's Horizon 2020 research and innovation program and EFPIA; the support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, Dutch Cardiovascular Alliance Double Dosis, 2020-B005; ZonMW-Metacor. MR was supported by a grant from the Gottfried and Julia Bangerter-Rhyner-Stiftung Switzerland and a grant from the University Hospital of Bern, Inselspital (Nachwuchsförderungs-Grant). KEO received funding by a grant from the Swiss National Science Foundation (SNF 310030_197595) and a Bern Center of Precision Medicine Lighthouse grant. PV received grants from The Netherlands CardioVascular Research Initiative (CVON 2017-13 VIGILANCE and CVON 2018-30 PREDICT2), Den Haag, The Netherlands, and the Health Foundation Limburg, Maastricht. RtB received grants from The Netherlands Organization for Scientific Research (Veni grant, 0915016181013), and the Health Foundation Limburg, Maastricht.

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