Ana Mincholé

Quantification of Restitution Dispersion From the Dynamic Changes of the

Action potential duration restitution (APDR) curves present spatial variations due to the electrophysiological heterogeneities present in the heart. Enhanced spatial APDR dispersion in ventricle has been suggested as an arrhythmic risk marker. In this study, we propose a method to noninvasively quantify dispersion of APDR slopes at tissue level by making only use of the surface electrocardiogram (ECG). The proposed estimate accounts for rate normalized differences in the steady-state T-wave peak to T-wave end interval (Tpe). A methodology is developed for its computation, which includes compensation for the Tpe memory lag after heart-rate (HR) changes. The capability of the proposed estimate to reflect APDR dispersion is assessed using a combination of ECG signal processing, and computational modeling and simulation. Specifically, ECG recordings of control subjects undergoing a tilt test trial are used to measure that estimate, while its capability to provide a quantification of APDR dispersion at tissue level is assessed by using a 2-D ventricular tissue simulation. From this simulation, APDR dispersion, denoted as ΔαSIM, is calculated, and pseudo-ECGs are derived. Estimates of APDR dispersion measured from the pseudo-ECGs show to correlate with ΔαSIM, being the mean relative error below 5%. A comparison of the ECG estimates obtained from tilt test recordings and the ΔαSIM values measured in silico simulations at tissue level show that differences between them are below 20%, which is within physiological variability limits. Our results provide evidence that the proposed estimate is a noninvasive measurement of APDR dispersion in ventricle. Additional results from this study confirm that Tpe adapts to HR changes much faster than the QT interval.

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Introduction Hypertrophic cardiomyopathy (HCM) is a cause of sudden arrhythmic death, but the understanding of its pro-arrhythmic mechanisms and an effective pharmacological treatment are lacking. HCM electrophysiological remodelling includes both increased inward and reduced outward currents, but their role in promoting repolarisation abnormalities remains unknown. The goal of this study is to identify key ionic mechanisms driving repolarisation abnormalities in human HCM, and to evaluate anti-arrhythmic effects of single and multichannel inward current blocks. Methods Experimental ionic current, action potential (AP) and Ca2 +-transient (CaT) recordings were used to construct populations of human non-diseased and HCM AP models (n = 9118), accounting for inter-subject variability. Simulations were conducted for several degrees of selective and combined inward current block. Results Simulated HCM cardiomyocytes exhibited prolonged AP and CaT, diastolic Ca2 + overload and decreased CaT amplitude, in agreement with experiments. Repolarisation abnormalities in HCM models were consistently driven by L-type Ca2 + current (ICaL) re-activation, and ICaL block was the most effective intervention to normalise repolarisation and diastolic Ca2 +, but compromised CaT amplitude. Late Na+ current (INaL) block partially abolished repolarisation abnormalities, with small impact on CaT. Na+/Ca2 + exchanger (INCX) block effectively restored repolarisation and CaT amplitude, but increased Ca2 + overload. Multichannel block increased efficacy in normalising repolarisation, AP biomarkers and CaT amplitude compared to selective block. Conclusions Experimentally-calibrated populations of human AP models identify ICaL re-activation as the key mechanism for repolarisation abnormalities in HCM, and combined INCX, INaL and ICaL block as effective anti-arrhythmic therapies also able to partially reverse the HCM electrophysiological phenotype.

-Wave Peak to End, Measured at the Surface ECG

Aims Acute ischemia is a major cause of sudden arrhythmic death, further promoted by potassium current blockers. Macro-reentry around the ischemic region and early afterdepolarizations (EADs) caused by electrotonic current have been suggested as potential mechanisms in animal and isolated cell studies. However, ventricular and human-specific arrhythmia mechanisms and their modulation by repolarization reserve remain unclear. The goal of this paper is to unravel multiscale mechanisms underlying the modulation of arrhythmic risk by potassium current (IKr) block in human ventricles with acute regional ischemia. Methods and results A human ventricular biophysically-detailed model, with acute regional ischemia is constructed by integrating experimental knowledge on the electrophysiological ionic alterations caused by coronary occlusion. Arrhythmic risk is evaluated by determining the vulnerable window (VW) for reentry following ectopy at the ischemic border zone. Macro-reentry around the ischemic region is the main reentrant mechanism in the ischemic human ventricle with increased repolarization reserve due to the ATP-sensitive potassium current (IK(ATP)) activation. Prolongation of refractoriness by 4% caused by 30% IKr reduction counteracts the establishment of macro-reentry and reduces the VW for reentry (by 23.5%). However, a further decrease in repolarization reserve (50% IKr reduction) is less anti-arrhythmic despite further prolongation of refractoriness. This is due to the establishment of transmural reentry enabled by electrotonically-triggered EADs in the ischemic border zone. EADs are produced by L-type calcium current (ICaL) reactivation due to prolonged low amplitude electrotonic current injected during the repolarization phase. Conclusions Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.

Mechanisms of pro-arrhythmic abnormalities in ventricular repolarisation and anti-arrhythmic therapies in human hypertrophic cardiomyopathy

Both biomedical research and clinical practice rely on complex datasets for the physiological and genetic characterization of human hearts in health and disease. Given the complexity and variety of approaches and recordings, there is now growing recognition of the need to embed computational methods in cardiovascular medicine and science for analysis, integration and prediction. This paper describes a Workshop on Computational Cardiovascular Science that created an international, interdisciplinary and inter-sectorial forum to define the next steps for a human-based approach to disease supported by computational methodologies. The main ideas highlighted were (i) a shift towards human-based methodologies, spurred by advances in new in silico, in vivo, in vitro, and ex vivo techniques and the increasing acknowledgement of the limitations of animal models. (ii) Computational approaches complement, expand, bridge, and integrate in vitro, in vivo, and ex vivo experimental and clinical data and methods, and as such they are an integral part of human-based methodologies in pharmacology and medicine. (iii) The effective implementation of multi- and interdisciplinary approaches, teams, and training combining and integrating computational methods with experimental and clinical approaches across academia, industry, and healthcare settings is a priority. (iv) The human-based cross-disciplinary approach requires experts in specific methodologies and domains, who also have the capacity to communicate and collaborate across disciplines and cross-sector environments. (v) This new translational domain for human-based cardiology and pharmacology requires new partnerships supported financially and institutionally across sectors. Institutional, organizational, and social barriers must be identified, understood and overcome in each specific setting.

Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve.

Background Increased spatial dispersion of restitution properties has been associated to arrhythmic risk. An ECG-based index quantifying restitution dispersion, DRest, is evaluated in patients who experienced Torsades de Pointes (TdP) under sotalol challenge and compared with the response in healthy subjects. Methods and Results ECG recordings were analyzed for quantification of DRest and QTc, among others biomarkers. DRest provides improved discrimination following sotalol administration between TdP and healthy subjects ([min–max]: [0.18–0.22] vs [0.02–0.12]), compared to other biomarkers including QTc ([436–548 ms] vs [376–467 ms]). Results in healthy subjects are in agreement with simulations of sotalol effects on a human tissue electrophysiological model. Conclusions This case study supports the potential of DRest for improved arrhythmia risk stratification even with QTc values below 450 ms.

Human-based approaches to pharmacology and cardiology: an interdisciplinary and intersectorial workshop

BACKGROUND Considering the rates of sudden cardiac death (SCD) and pump failure death (PFD) in chronic heart failure (CHF) patients and the cost-effectiveness of their preventing treatments, identification of CHF patients at risk is an important challenge. In this work, we studied the prognostic performance of the combination of an index potentially related to dispersion of repolarization restitution (Δα), an index quantifying T-wave alternans (IAA) and the slope of heart rate turbulence (TS) for classification of SCD and PFD. METHODS Holter ECG recordings of 597 CHF patients with sinus rhythm enrolled in the MUSIC study were analyzed and Δα, IAA and TS were obtained. A strategy was implemented using support vector machines (SVM) to classify patients in three groups: SCD victims, PFD victims and other patients (the latter including survivors and victims of non-cardiac causes). Cross-validation was used to evaluate the performance of the implemented classifier. RESULTS Δα and IAA, dichotomized at 0.035 (dimensionless) and 3.73 μV, respectively, were the ECG markers most strongly associated with SCD, while TS, dichotomized at 2.5 ms/RR, was the index most strongly related to PFD. When separating SCD victims from the rest of patients, the individual marker with best performance was Δα≥0.035, which, for a fixed specificity (Sp) of 90%, showed a sensitivity (Se) value of 10%, while the combination of Δα and IAA increased Se to 18%. For separation of PFD victims from the rest of patients, the best individual marker was TS ≤ 2.5 ms/RR, which, for Sp=90%, showed a Se of 26%, this value being lower than Se=34%, produced by the combination of Δα and TS. Furthermore, when performing SVM classification into the three reported groups, the optimal combination of risk markers led to a maximum Sp of 79% (Se=18%) for SCD and Sp of 81% (Se=14%) for PFD. CONCLUSIONS The results shown in this work suggest that it is possible to efficiently discriminate SCD and PFD in a population of CHF patients using ECG-derived risk markers like Δα, TS and IAA.

ECG-based estimation of dispersion of APD restitution as a tool to stratify sotalol-induced arrhythmic risk

Background Patients with chronic heart failure are at high risk of sudden cardiac death (SCD). Increased dispersion of repolarization restitution has been associated with SCD, and we hypothesize that this should be reflected in the morphology of the T‐wave and its variations with heart rate. The aim of this study is to propose an electrocardiogram (ECG)‐based index characterizing T‐wave morphology restitution (TMR), and to assess its association with SCD risk in a population of chronic heart failure patients. Methods and Results Holter ECGs from 651 ambulatory patients with chronic heart failure from the MUSIC (MUerte Súbita en Insuficiencia Cardiaca) study were available for the analysis. TMR was quantified by measuring the morphological variation of the T‐wave per RR increment using time‐warping metrics, and its predictive power was compared to that of clinical variables such as the left ventricular ejection fraction and other ECG‐derived indices, such as T‐wave alternans and heart rate variability. TMR was significantly higher in SCD victims than in the rest of patients (median 0.046 versus 0.039, P<0.001). When TMR was dichotomized at TMR=0.040, the SCD rate was significantly higher in the TMR≥0.040 group (P<0.001). Cox analysis revealed that TMR≥0.040 was strongly associated with SCD, with a hazard ratio of 3.27 (P<0.001), independently of clinical and ECG‐derived variables. No association was found between TMR and pump failure death. Conclusions This study shows that TMR is specifically associated with SCD in a population of chronic heart failure patients, and it is a better predictor than clinical and ECG‐derived variables.

Automatic SVM classification of sudden cardiac death and pump failure death from autonomic and repolarization ECG markers.

Abstract ST segment changes provide a sensitive marker in the diagnosis of myocardial ischemia in Holter recordings. However, not only do the mechanisms of ischemia result in ST segment deviation, but also heart rate related episodes, body position changes or conduction changes among others, which are considered artifactual events when ischemia is the target. In order to distinguish between them, the very similar signatures of ST modifications has led us to look for other ECG indices such as heart rate-based indices, correlation between the absolute ST segment deviation and heart rate series, the interval between the T apex and the T end , T wave amplitude, the signal-to-noise ratio and changes in the upward/downward slopes of the QRS complex. A discrimination analysis between the three types of events: ischemia, heart rate related episodes and sudden step ST changes (body position changes and conduction changes) has been performed on the Long-Term ST Database, reaching an accuracy of 82.3%. If we focus on distinguishing between different ST signatures, transient episodes (ischemic and heart rate related) and sudden step ST changes, it results in a sensitivity of 76.8% and a specificity of 98.3%. When classifying ischemia from heart rate related episodes, both with a very similar ST level pattern, a sensitivity of 84.5% and a specificity of 86.6% are reached. Finally, for separating ischemia from any other ST event, a sensitivity of 74.2% and a specificity of 93.2% are obtained.

T‐Wave Morphology Restitution Predicts Sudden Cardiac Death in Patients With Chronic Heart Failure

In this work we revisit an ischemia detector based on the root mean square (RMS) series of the repolarization interval developed and validated using the European Society of cardiology ST-T database (ESCDB). This detector, developed within this database framework, gets sensitivity (S)/positive predictivity (+P) performance figures of 85%/86%. Our aim now is to re-evaluate the detector in the much richer long-term ST database where ST episodes of different origin are present, making a much more challenging scenario for the detector. Just a straight forward adaptation of the RMS detector reduces its performance figures, S/+P, to 70%/68%. This, apart from other reasons, is a consequence of the presence in the database of ST episodes generated by body position changes (BPC) which can be misinterpreted. A BPC detector incorporated to the previous detector noticeably improves the figures up to 75%/71%

Discrimination Between Ischemic and Artifactual ST Segment Events in Holter Recordings

Body position changes (BPC), which are often manifested in the ECG as shifts in the electrical axis of the heart, result in ST changes, and thus, may be misclassified as ischemic events during ambulatory monitoring. We have developed a BPC detector by modeling shifts as changes in the Karhunen-Loève transform coefficients of the QRS complex and the ST-T waveform. The noise is assumed to have a Laplacian distribution. A generalized likelihood ratio test has been chosen as the strategy to detect BPCs. Two different databases have been used to assess detection performance. The obtained results were 93%/99% in terms of sensitivity/positive predictivity value (S/+PV) and a false alarm rate of 2 events/hour. The results clearly outperform current techniques (S/+PV: 85%/99%) based on the Gaussian noise assumption.