Cardiac arrhythmias are a common cause of sudden death worldwide. However, despite decades of thorough investigation the underlying biophysical mechanisms of cardiac arrhythmias are still... Show moreCardiac arrhythmias are a common cause of sudden death worldwide. However, despite decades of thorough investigation the underlying biophysical mechanisms of cardiac arrhythmias are still insufficiently understood due to incomplete theories and the lack of precise spatiotemporal control in experiments. In the last decade, the problem of insufficient spatiotemporal control has started to be tackled by means of a new technique, called optogenetics. This technique employs expression of light-activated proteins, which are activated or deactivated in time and space by switching on/off light (in the near-ultraviolet to near-infrared wavelength range) in specific patterns thus realizing fully biological spatiotemporal control. However, with a few notable exceptions, cardiac optogenetic studies have only confirmed previously known mechanisms and yielded no or little novel mechanistic insights. In this thesis, to fill this gap, we combined nonlinear dynamics theory, numerical simulations and optogenetic experiments with unique spatiotemporal control to theoretically predict and demonstrate novel arrhythmogenic phenomena in cardiac tissue. Thanks to the robustness of the optogenetics methods and generality of the applied theories and computations, this thesis uncovered novel mechanisms for the biophysics of cardiac tissue that are applicable to the functioning of excitable systems in general. Show less
Background: QTc-prolongation is an independent risk factor for developing life-threatening arrhythmias. Risk management of drug-induced QTc-prolongation is complex and digital support tools could... Show moreBackground: QTc-prolongation is an independent risk factor for developing life-threatening arrhythmias. Risk management of drug-induced QTc-prolongation is complex and digital support tools could be of assistance. Bindraban et al. and Berger et al. developed two algorithms to identify patients at risk for QTc-prolongation.Objective: The main aim of this study was to compare the performances of these algorithms for managing QTcprolonging drug-drug interactions (QT-DDIs).Materials and Methods: A retrospective data analysis was performed. A dataset was created from QT-DDI alerts generated for inand outpatients at a general teaching hospital between November 2016 and March 2018. ECGs recorded within 7 days of the QT-DDI alert were collected. Main outcomes were the performance characteristics of both algorithms. QTc-intervals of > 500 ms on the first ECG after the alert were taken as outcome parameter, to which the performances were compared. Secondary outcome was the distribution of risk scores in the study cohort.Results: In total, 10,870 QT-DDI alerts of 4987 patients were included. ECGs were recorded in 26.2 % of the QT-DDI alerts. Application of the algorithms resulted in area under the ROC-curves of 0.81 (95 % CI 0.79-0.84) for Bindraban et al. and 0.73 (0.70-0.75) for Berger et al. Cut-off values of >= 3 and >= 6 led to sensitivities of 85.7 % and 89.1 %, and specificities of 60.8 % and 44.3 % respectively.Conclusions: Both algorithms showed good discriminative abilities to identify patients at risk for QTcprolongation when using >= 2 QTc-prolonging drugs. Implementation of digital algorithms in clinical decision support systems could support the risk management of QT-DDIs. Show less
Zandstra, T.; Kies, P.; Man, S.C.; Maan, A.; Bootsma, M.; Vliegen, H.; ... ; Jongbloed, M. 2020
Background: QT interval variability (QTV) and heart rate turbulence (HRT) are measures of cardiac autonomic function, which, when abnormal, are correlated with ventricular arrhythmias and worse... Show moreBackground: QT interval variability (QTV) and heart rate turbulence (HRT) are measures of cardiac autonomic function, which, when abnormal, are correlated with ventricular arrhythmias and worse clinical outcome. This study aims to evaluate QTV and HRT in patients with a systemic right ventricle (RV) and to assess correlations with clinical characteristics.Methods: In a retrospective cohort study, QTV and HRT were derived from 24-h Holter registrations of patients with a systemic RV and healthy controls. QTV and HRT were compared between groups. In patients, the association between QTV, HRT, and clinical characteristics was assessed.Results: Holter recordings from 40 patients (mean age 40 years, 16 females) and 37 healthy controls (mean age 42 years, 21 females) were analyzed. Groups were comparable in terms of age and sex. QTV was increased in patients compared with controls (p < 0.001), HRT did not differ significantly between the groups. Increased QTV and decreased HRT correlated with medication use, especially of diuretics, and with clinical events, particularly supraventricular arrhythmias. Increased QTV correlated with reduced systemic RV function. Decreased HRT was independently associated with a larger number of past clinical events (estimate -0.33, 95% CI -0.63 to -0.02, p = 0.037). QTV was higher in women in both patients and controls (p = 0.041 and p = 0.034, respectively).Conclusions: QTV and HRT are associated with clinical factors and events in patients with a systemic RV. Further studies are mandatory to confirm their prognostic value. (C) 2020 Published by Elsevier Ltd on behalf of Japanese College of Cardiology. Show less
Clinicians accept that there are many unknowns when we make diagnostic and therapeutic decisions. Acceptance of uncertainty is essential for the pursuit of the profession: bedside decisions must... Show moreClinicians accept that there are many unknowns when we make diagnostic and therapeutic decisions. Acceptance of uncertainty is essential for the pursuit of the profession: bedside decisions must often be made on the basis of incomplete evidence. Over the years, physicians sometimes even do not realize anymore which the fundamental gaps in our knowledge are. As clinical scientists, however, we have to halt and consider what we do not know yet, and how we can move forward addressing those unknowns. The European Heart Rhythm Association (EHRA) believes that scanning the field of arrhythmia / cardiac electrophysiology to identify knowledge gaps which are not yet the subject of organized research, should be undertaken on a regular basis. Such a review (White Paper) should concentrate on research which is feasible, realistic, and clinically relevant, and should not deal with futuristic aspirations. It fits with the EHRA mission that these White Papers should be shared on a global basis in order to foster collaborative and needed research which will ultimately lead to better care for our patients. The present EHRA White Paper summarizes knowledge gaps in the management of atrial fibrillation, ventricular tachycardia/sudden death and heart failure. Show less
Cardiac arrhythmias are one of the major causes of morbidity and mortality in the world. The clinical management of cardiac arrhythmias relies on several anti-arrhythmic therapies, e.g. drugs,... Show moreCardiac arrhythmias are one of the major causes of morbidity and mortality in the world. The clinical management of cardiac arrhythmias relies on several anti-arrhythmic therapies, e.g. drugs, ablation, and device implantation that, unfortunately, are often unspecific, irreversible and/or traumatizing, respectively. Recently, to overcome these side effects, gene therapy has been introduced as an alternative option to treat cardiac arrhythmias by specifically targeting the biological defect. However, gene therapy alone is lacking the possibility to gain precise spatiotemporal and quantitative control over a certain target. Interestingly, more recently, such precise control could be achieved with an innovative strategy, called optogenetics. Here, gene therapy is combined with optics allowing expression of light-activatable proteins that are specifically activate and deactivate by simply turning light on and off, respectively. This now opens new and unique possibilities for cardiac arrhythmias research based on optical modulation of excitability with superb spatiotemporal resolution. Therefore, in the studies presented in this thesis, the unique features of optogenetics were employed for investigating the underlying mechanism of arrhythmia initiation, maintenance, and termination in order to identify novel biological anti-arrhythmic strategies. Show less
Cardiac tachyarrhythmias are a vast contributor to morbidity and mortality worldwide. Still, the mechanisms underlying these arrhythmias are incompletely understood. As a result, many of the... Show moreCardiac tachyarrhythmias are a vast contributor to morbidity and mortality worldwide. Still, the mechanisms underlying these arrhythmias are incompletely understood. As a result, many of the treatment options available for these arrhythmias rely on sole alleviation of symptoms or prevention of complications secondary to the arrhythmia, or are associated with non-trivial adverse effects. An increased understanding of the mechanisms underlying cardiac tachyarrhythmias as well as the means to reverse them is a critical prerequisite if we are to shift towards more specific, more effective and less harmful arrhythmia treatment. Therefore, the research described in this thesis investigates the molecular and cellular determinants of cardiac tachyarrhythmias in ex vivo and in vitro models of cardiac hypertropfy/fibrosis, ventricular fibrillation and atrial fibrillation using state of the art electrophysiological and genetic tools. Show less
