When Manual Analysis of 12-Lead ECG Holter Plays a Critical Role in Discovering Unknown Patterns of Increased Arrhythmogenic Risk: A Case Report of a Patient Treated with Tamoxifen and Subsequent Pneumonia in COVID-19

Donatella Brisinda,Barbara Merico,Riccardo Fenici,Peter Fenici

doi:10.1007/s12012-021-09659-w

Abstract

Several medicines, including cancer therapies, are known to alter the electrophysiological function of ventricular myocytes resulting in abnormal prolongation and dispersion of ventricular repolarization (quantified by multi-lead QTc measurement). This effect could be amplified by other concomitant factors (e.g., combination with other drugs affecting the QT, and/or electrolyte abnormalities, such as especially hypokalemia, hypomagnesaemia, and hypocalcemia). Usually, this condition results in higher risk of torsade de point and other life-threatening arrhythmias, related to unrecognized unpaired cardiac ventricular repolarization reserve (VRR). Being VRR a dynamic phenomenon, QT prolongation might often not be identified during the 10-s standard 12-lead ECG recording at rest, leaving the patient at increased risk for life-threatening event. We report the case of a 49-year woman, undergoing tamoxifen therapy for breast cancer, which alteration of ventricular repolarization reserve, persisting also after correction of concomitant recurrent hypokalemia, was evidenced only after manual measurements of the corrected QT (QTc) interval from selected intervals of the 12-lead ECG Holter monitoring. This otherwise missed finding was fundamental to drive the discontinuation of tamoxifen, shifting to another “safer” therapeutic option, and to avoid the use of potentially arrhythmogenic antibiotics when treating a bilateral pneumonia in recent COVID-19.

Highlights

Drug-induced prolongation of ventricular repolarization is the most common and preventable cause of the so-called secondary Long QT syndrome (LQTS), which may imply high risk of life-threatening ventricular arrhythmic events [1,2,3]
Prolonged tamoxifen treatment is usually monitored with periodical standard 12-lead ECG to exclude drug-induced side effects on ventricular repolarization [5, 12]. This approach is considered sufficiently sensitive, and Holter monitoring of QTc interval duration is usually not recommended [4] because the complexity of the physiological control of circadian modulation of ventricular repolarization rate dependence has not been yet fully clarified and the range of normality and reproducibility of QTc values under dynamic conditions are still uncertain [19,20,21], we found that it was useful to discover otherwise unknown dynamic abnormality of the QTc interval, suggestive of impaired ventricular repolarization reserve (VRR), primarily determined by tamoxifen and requiring its discontinuation, the oncologist favored that drug as first choice
In the reported case, the QTc prolongation frequently exceeded 500 ms, major high-risk LQT syndromes were ruled out by the negative results of genetic tests and only rare single premature ventricular beats were observed. This suggests that, impaired and generating transient ECG abnormality, the patient’s VRR was still sufficient to prevent the occurrence of dangerous ventricular arrhythmias and that probably a minor ion channel dysfunction has been unmasked only eventually by the overlapping of external factors such as tamoxifen-induced block of the IKr, enhanced by recurrent hypokalemia and only partially compensated by a gain of function of the IKs channel [5]

Summary

Introduction

Drug-induced prolongation of ventricular repolarization is the most common and preventable cause of the so-called secondary Long QT syndrome (LQTS), which may imply high risk of life-threatening ventricular arrhythmic events [1,2,3]. One week later (May 7th), rest QTc was within normal limits (see Fig. 1, in the supplementary information), in spite of recurrent hypokalemia (K+ plasma level 3.3 mmol/l— the patient had self-discontinued potassium supplement and antialdosteronic therapy), but transient phases of QTc prolongation (up to 523 ms) were still appreciable at 12-lead Holter monitoring, which in addition evidenced persistence of other VR abnormalities (Fig. 3b). 2. Corresponding 12-lead Holter recordings evidenced clear-cut VR abnormalities with prolongation of QTc values (calculated with three normalization methods), during phases of sympathetic enhancement, especially at wake-up, and HR increase (range of QTcB: 499–595 ms; QTcF: 475–542 ms; QTcH: 484–528), (Table 1 in supplementary information). No significant QTc prolongation nor arrhythmia were observed during the hospitalization

Findings

Discussion

Conclusion