Techniques for ventricular repolarization instability assessment from the ECG

Instabilities in ventricular repolarization have been documented to be tightly linked to arrhythmia vulnera- bility. Translation of the information contained in the repolar- ization phase of the electrocardiogram (ECG) into valuable clinical decision-making tools remains challenging. This work aims at providing an overview of the last advances in the pro- posal and quantification of ECG-derived indices that describe repolarization properties and whose alterations are related with threatening arrhythmogenic conditions. A review of the state of the art is provided, spanning from the electrophysio- logical basis of ventricular repolarization to its characteriza- tion on the surface ECG through a set of temporal and spatial risk markers

ADAPTIVE MODELS-BASED CARDIAC SIGNALS ANALYSIS AND FEATURE EXTRACTION

Signal modeling and feature extraction are among the most crucial and important steps for stochastic signal processing. In this thesis, a general framework that employs adaptive model-based recursive Bayesian state estimation for signal processing and feature extraction is described. As a case study, the proposed framework is studied for the problem of cardiac signal analysis. The main objective is to improve the signal processing aspects of cardiac signals by developing new techniques based on adaptive modelling of electrocardiogram (ECG) wave-forms. Specially several novel and improved approaches to model-based ECG decomposition, waveform characterization and feature extraction are proposed and studied in detail. In the concept of ECG decomposition and wave-forms characterization, the main idea is to extend and improve the signal dynamical models (i.e. reducing the non-linearity of the state model with respect to previous solutions) while combining with Kalman smoother to increase the accuracy of the model in order to split the ECG signal into its waveform components, as it is proved that Kalman filter/smoother is an optimal estimator in minimum mean square error (MMSE) for linear dynamical systems. The framework is used for many real applications, such as: ECG components extraction, ST segment analysis (estimation of a possible marker of ventricular repolarization known as T/QRS ratio) and T-wave Alternans (TWA) detection, and its extension to many other applications is straightforward. Based on the proposed framework, a novel model to characterization of Atrial Fibrillation (AF) is presented which is more effective when compared with other methods proposed with the same aims. In this model, ventricular activity (VA) is represented by a sum of Gaussian kernels, while a sinusoidal model is employed for atrial activity (AA). This new model is able to track AA, VA and fibrillatory frequency simultaneously against other methods which try to analyze the atrial fibrillatory waves (f-waves) after VA cancellation. Furthermore we study a new ECG processing method for assessing the spatial dispersion of ventricular repolarization (SHVR) using V-index and a novel algorithm to estimate the index is presented, leading to more accurate estimates. The proposed algorithm was used to study the diagnostic and prognostic value of the V-index in patients with symptoms suggestive of Acute Myocardial Infraction (AMI)

Advances in Digital Processing of Low-Amplitude Components of Electrocardiosignals

This manual has been published within the framework of the BME-ENA project under the responsibility of National Technical University of Ukraine. The BME-ENA “Biomedical Engineering Education Tempus Initiative in Eastern Neighbouring Area”, Project Number: 543904-TEMPUS-1-2013-1-GR-TEMPUS-JPCR is a Joint Project within the TEMPUS IV program. This project has been funded with support from the European Commission.Навчальний посібник присвячено розробці методів та засобів для неінвазивного виявлення та дослідження тонких проявів електричної активності серця. Особлива увага приділяється вдосконаленню інформаційного та алгоритмічного забезпечення систем електрокардіографії високого розрізнення для ранньої діагностики електричної нестабільності міокарда, а також для оцінки функціонального стану плоду під час вагітності. Теоретичні основи супроводжуються прикладами реалізації алгоритмів за допомогою системи MATLAB. Навчальний посібник призначений для студентів, аспірантів, а також фахівців у галузі біомедичної електроніки та медичних працівників.The teaching book is devoted to development and research of methods and tools for non-invasive detection of subtle manifistations of heart electrical activity. Particular attention is paid to the improvement of information and algorithmic support of high resolution electrocardiography for early diagnosis of myocardial electrical instability, as well as for the evaluation of the functional state of the fetus during pregnancy examination. The theoretical basis accompanied by the examples of implementation of the discussed algorithms with the help of MATLAB. The teaching book is intended for students, graduate students, as well as specialists in the field of biomedical electronics and medical professionals

Estimation of Serum Potassium and Calcium Concentrations from Electrocardiographic Depolarization and Repolarization Waveforms

Chronic kidney disease (CKD), a condition defined by a gradual decline in kidney function over time, has become a global health concern affecting between 11 and 13% of the world population [1]. As renal function declines, CKD patients gradually lose their ability to maintain normal values of potassium concentration ([K+]) in their blood. Elevated serum [K+], known as hyperkalemia, increases the risk for life-threatening arrhythmias and sudden cardiac death [2].An increase in serum [K+] outside the physiological range is commonly silent and is only detected when hyperkalemia is already very severe or when a blood test is performed. Maintenance and monitoring of [K+] in the blood is an important component in the treatment of CKD patients because therapies for hyperkalemia management in CKD patients are designed to prevent arrhythmias and to immediately lower serum [K+] to safe ranges. However, this is currently only possible by taking a blood sample and is associated with a long analysis time. Therefore it is useful to have a simple, noninvasive method to estimate serum [K+], particularly using the electrocardiogram (ECG). Indeed, variations in serum electrolyte levels have been shown to alter the electrical behavior of the heart and to induce changes in the ECG [3¿6]. However, large inter-individual variability existsin the relationship between ion concentrations and ECG features. Previous attempts to estimate serum [K+] from the ECG have therefore shown limitations [7¿9], such as not being applicable to some common types of ECG waveforms or relying on specific ECG characteristics that may present large variations not necessarily associated with hyperkalemia.The aim of this thesis is to develop novel estimates of serum [K+] that are robust enough to detect hypokalemia (reduced [K+]) or hyperkalemia in a timely manner to provide life-saving treatment. Additionally, the effect of changes in other electrolyte levels, like calcium concentration ([Ca2+]), and in heart rate are investigated. These aims are achieved by combining novel ECG signal processing techniques with in silico modeling and simulation of cardiac electrophysiology.The specific objectives are:1. Characterization of hypokalemia or hyperkalemia and hypocalcemia (reduced [Ca2+]) or hypercalcemia (elevated [Ca2+])-induced changes in ventricular repolarization from ECGs (T wave) of CKD patients. This is addressed in chapter 3 and chapter 4. In these chapters, we describe how T waves are extracted from ECGs and how we characterize changes in T waves at varying potassium, calcium and heart rate using analyses based on time warping and Lyapunov exponents. Next, univariable and multivariable regression models including markers of T wave nonlinear dynamics in combination with warping-based markers of T wave morphology are built and their performance for [K+] estimation is assessed.2. Characterization of hypo- or hyperkalemia and hypo- or hypercalcemia-induced changes in ventricular depolarization from the QRS complex of CKD patients. This is reported in chapter 5. In this chapter, we present how QRS complexes from ECGs of CKD patients are processed and how we measure changes at varying [K+], [Ca2+] and heart rate. Univariate and multivariate regression analyses including novel QRS morphological markers in combination with T wave morphological markers are performed to assess the contribution of depolarization and repolarization features for electrolyte monitoring in CKD patients.3. Identification of potential sources underlying inter-individual variability in ECG markers in response to changes in [K+] and [Ca2+]. In silico investigations of cardiac electrophysiology are conducted and ECG features are computed. Simulation results are compared with patient data. This is explained in chapter 3 using one-dimensional (1D) fibers and in chapter 6 using three-dimensional (3D) human heart-torso models. Chapter 6 includes the development of a population of realistic computational models of human ventricular electrophysiology, based on human anatomy and electrophysiology, to better understand how changes in individual characteristics influence the ECG (QRS and T wave) markers that we introduced in previous chapters. ECG waveforms are characterized by their amplitude, duration and morphology. Simulations are performed with the most realistic available techniques to model the electrophysiology of the heart and the resulting ECG. We establish mechanisms that contribute to inter-individual differences in the characterized ECG features.In conclusion, we identify several markers of ECG morphology, including depolarization and repolarization features, that are highly correlated with serum electrolyte (potassium and calcium) concentrations. ECG morphological variability markers vary significantly with [K+] and [Ca2+] in both simulated and measured ECGs, with a wide range of patterns observed for such relationships. The proportions of endocardial, midmyocardial and epicardial cells have a large impact on ECG markers, particularly for serum electrolyte concentrations out of their physiological levels. This suggests that transmural heterogeneities can modulate ECG responses to changes in electrolyte concentrations in CKD patients. Agreement between actual potassium and calcium levels and their estimates derived from the ECG is promising, with lower average errors than previously proposed markers in the literature. These findings can have major relevance for noninvasive monitoring of serum electrolyte levels and prediction of arrhythmic events in these patients.<br /

Arrhythmia mechanisms in acute ischaemia and chronic infarction in rabbit heart

In this thesis, a method for studying the electrophysiological consequences of acute regional ischaemia in rabbit heart was established using a combination of a novel snare technique and optical mapping. The purpose of this approach was to discover the mechanistic link between acute coronary infarction and the occurrence of arrhythmias. The electrophysiology of the epicardial surface of isolated hearts was examined using the voltage sensitive dye RH237 and optical action potentials were recorded from a 13x13mm area of left ventricular epicardium using a 16x16 element Hamamatsu photodiode array. Contraction motion artefacts were practically eliminated with blebbistatin (5µM). An alternative mechanical uncoupler, BDM, was found to be not suitable for the study of arrhythmic behaviour associated with ischaemia. After occlusion of the left coronary artery, a progressive reduction in action potential duration (APD), and slowing of upstroke was observed in an area of the left ventricle anterior surface, accompanied by ECG S-T segment elevation. These effects were reversed when the coronary artery occlusion was released. Ligation (duration 12-15mins) caused a decrease in APD50 (APD at 50% repolarisation), in the zone of reduced perfusion, from 141±5.2ms to 53.3±9.3ms (mean±SEM, n=10 hearts, P<0.001). After ligation was reversed and full perfusion restored, APD50 returned to normal values (149±7.0ms, n.s.). Trise (action potential rise time from 10-90% depolarisation) increased from 7.2±1.0ms to 15.8±2.8ms (P<0.01). In the non-infarcted area of myocardium, no significant changes in APD50 (147±7.0ms vs. 147±8.1ms) or Trise (6.4±0.4ms vs 8.8±1.4ms) were observed during occlusion. T-wave alternans behaviour was observed frequently during local ischaemia and associated with alternans of optical action potentials (OAPs) in the ischaemic border zone (BZ) and in ischaemic zone (IZ). T-wave alternans amplitude was not maintained during local ischaemia but OAPs continued to show alternating behaviour. Arrhythmias (VT and VF) were common when conduction block occurred at the interface between the normal and ischaemic zone, but arrhythmias were absent when conduction into the IZ was retained. This observation suggests that the conduction block was the crucial precipitating event for the generation of arrhythmias. Acute local ischaemia was also imposed in a heart with an existing infarct scar to examine the effects of pre-existing ischaemic damage. The incidence of arrhythmias was similar to that observed in the absence of an infarct scar indicating that pre-existing damage did not predispose the heart to arrhythmias. Global ischaemic challenges, both low flow and zero flow produced similar reductions in APD and rise time and were followed by arrhythmias, but the associated changes in the ECG were complex and could not be easily interpreted. Significant temporal variability in electrophysiology was observed in global ischaemia, but absent in the local ischaemic challenge. The underlying mechanisms of these temporal flucuations in cardiac electrophysiology may be dictated by either cellular metabolism or fluctuations in coronary flow. Long-term local ischaemia (~60mins) did not reveal a second phase of arrhythmias after 40-45mins as observed in other animal models, and nor were there signs of significant further electrophysiological changes as a consequence of the additional period of local ischaemia

SPATIO-TEMPORAL VARIATION IN ACTIVATION INTERVALS DURING VENTRICULAR FIBRILLATION

Spatio-temporal variation in activation rates during ventricular fibrillation (VF)provides insight into mechanisms of sustained re-entry during VF. This study had three objectives related to spatio-temporal dynamics in activation rates during VF. The first objective was to quantify spatio-temporal variability in activation rates,that is, in dominant frequencies, computed from epicardial electrograms recorded during VF in swine. Results showed that temporally and spatially, dominant frequencies variedas much as 20% of the mean dominant frequency, and the mean dominant frequencies increased during first 30 sec of VF. These results suggest that activation rates are nonstationary during VF. The second objective of the study was to develop a new stimulation protocol for quantifying restitution of action potential duration (APD) by independently controlling diastolic intervals (DI). A property of cardiac cells that determines spatio-temporal variability in dominant frequencies is restitution of APD, which relates APD to the previous DI. Independent control of DI permits explicit determination of the role of memory in restitution. Restitution functions quantified using mathematical models of activation and our stimulation protocol, showed significant hysteresis. That is, for adiastolic interval, the action potential durations were as much as 15% longer during periods when the DI were decreasing than when the DI were increasing. We verified the feasibility of implementing our protocol experimentally in isolated and perfused rat hearts with action potentials recorded using floating glass microelectrodes. The third objective of our study was to verify that spatio-temporal variability in dominant frequencies during VF could be modified using spatially distributed pacing strength stimuli. Simulated VF was induced in 400x400 and 400x800 matrices of cells. Electrical function of cells was simulated using the Luo-Rudy model. Stimulators were arranged in the matrices such that there were 5 rows of line stimulators. Results showed that it was possible to modify activations in almost 54% of the area and to modify spatio-temporal variability in activation during VF into a desired pattern by the use of synchronized pacing from multiple sites. These results support further exploration of distributed stimulation approach for potential improvements in defibrillation therapy

Genotype-Phenotype Relationships in Long QT Syndrome : Role of Mental Stress, Adrenergic Activity and a Common KCNH2 Polymorphism

Long QT syndrome is a congenital or acquired arrhythmic disorder which manifests as a prolonged QT-interval on the electrocardiogram and as a tendency to develop ventricular arrhythmias which can lead to sudden death. Arrhythmias often occur during intense exercise and/or emotional stress. The two most common subtypes of LQTS are LQT1, caused by mutations in the KCNQ1 gene and LQT2, caused by mutations in the KCNH2 gene. LQT1 and LQT2 patients exhibit arrhythmias in different types of situations: in LQT1 the trigger is usually vigorous exercise whereas in LQT2 arrhythmia results from the patient being startled from rest. It is not clear why trigger factors and clinical outcome differ from each other in the different LQTS subtypes. It is possible that stress hormones such as catecholamines may show different effects depending on the exact nature of the genetic defect, or sensitivity to catecholamines varies from subject to subject. Furthermore, it is possible that subtle genetic variants of putative modifier genes, including those coding for ion channels and hormone receptors, play a role as determinants of individual sensitivity to life-threatening arrhythmias. The present study was designed to identify some of these risk modifiers. It was found that LQT1 and LQT2 patients show an abnormal QT-adaptation to both mental and physical stress. Furthermore, as studied with epinephrine infusion experiments while the heart was paced and action potentials were measured from the right ventricular septum, LQT1 patients showed repolarization abnormalities which were related to their propensity to develop arrhythmia during intense, prolonged sympathetic tone, such as exercise. In LQT2 patients, this repolarization abnormality was noted already at rest corresponding to their arrhythmic episodes as a result of intense, sudden surges in adrenergic tone, such as fright or rage. A common KCNH2 polymorphism was found to affect KCNH2 channel function as demonstrated by in vitro experiments utilizing mammalian cells transfected with the KCNH2 potassium channel as well as QT-dynamics in vivo. Finally, the present study identified a common β-1-adrenergic receptor genotype that is related a shorter QT-interval in LQT1 patients. Also, it was discovered that compound homozygosity for two common β-adrenergic polymorphisms was related to the occurrence of symptoms in the LQT1 type of long QT syndrome. The studies demonstrate important genotype-phenotype differences between different LQTS subtypes and suggest that common modifier gene polymorphisms may affect cardiac repolarization in LQTS. It will be important in the future to prospectively study whether variant gene polymorphisms will assist in clinical risk profiling of LQTS patients.Pitkä QT -oireyhtymä on perinnöllinen sairaus, johon liittyy vakavia sydämen rytmihäiriöitä Oireyhtymä voi tunnistamattomana tai hoitamattomana johtaa odottamattomaan äkkikuolemaan.: Suomessa arvioidaan olevan ainakin 2000 pitkä QT -potilasta. Pitkä QT -oireyhtymä johtuu sydänlihassolun poikkeavan hitaasta sähköarsytyksen jälkeisestä palautumisvaiheesta (repolarisaatiosta), joka havaitaan EKG:ssa pidentyneenä Q-aikana. Sydämen repolarisaatio perustuu kaliumkanavien toimintaan, ja kalium-ionivirrat vastaavatkin pääasiassa sydänlihassolun paluusta lepotilaan. Kaksi yleisintä pitkä QT -oireyhtymän perinnöllistä alatyyppiä johtuvat puolestaan sydänlihassolun kaliumkanavia koodittavien geenien mutaatioista. Nämä geenit ovat KCNQ1 (taudin alatyyppi LQT1) ja KCNH2 (alatyyppi LQT2). Vaikka tiedetään että toiset LQT1 ja LQT2 -potilaat saavat rytmihäiriöitä muita herkemmin, mekanismia ei vielä tiedetä. Mutta altistavissa tekijöissä on tärkeitä eroja: LQT1-potilaiden rytmihäiriöt ilmenevät useimmiten fyysisen rasituksen aikana, kun taas LQT2-potilaiden rytmihäiriöt esiintyvät äkillisen psyykkisen ärsykkeen, esimerkiksi pelästymisen, seurauksena. Väitöskirjatyössä pyrittiin selvittämään, mistä nämä erot johtuvat. Väitöskirjatyön ensimmäisessä osatyössä selvitettiin, miten terveiden koehenkilöiden, LQT1-potilaiden ja LQT2-potilaiden QT-aika eroaa voimakkaan kokeellisen psyykkisen rasituksen ja fyysisen rasituksen aikana. Sekä LQT1- että LQT2-potilailla oli pidempi QT-aika kuin kontrolleilla, mutta näitä potilasryhmiä ei kuitenkaan pystytty erottelemaan toisistaan QT-ajan perusteella. Toisessa osatyössä mitattiin kontrollien, LQT1- ja LQT2 -potilaiden sähköisten impulssien kestoa ja muotoa sydämen oikeasta kammiosta. Tuloksena havaittiin, että aktiopotentiaalin muodon perusteella LQT2-potilaat ovat herkkiä rytmihäiriöille levossa, kun taas LQT1-potilailla ilmaantui rytmihäiriöille altistava muutos vasta stressihormoni adrenaliinin vaikutuksesta. Kolmannessa osatyössä selvitettiin yleisimmän tunnetun KCNH2-polymorfismin vaikutusta kyseisen kaliumkanavan toimintaan. Havaittiin, että kanavan harvinaisempi variantti (897T) toimi heikommin kuin yleisempi muoto ja siihen liittyi myös pidempi QT-aika. Viimeisessä osatyössä määritettiin, miten kaksi yleistä β1-adrenoseptorin polymorfiaa vaikuttaa LQT1-potilaiden QT-aikaan ja rytmihäiriöherkkyyteen. Niillä potilailla, joilla oli biologisesti aktiivisempaa β1-reseptoria vastaava geenivariantti, QT-aika oli lyhempi. Potilaat, jotka kantoivat samanaikaisesti kahta aktiivista reseptorityyppiä, olivat kaikkein alttiimpia rytmihäiriöille. Väitöskirjatyössä pystyttiin siis havaitsemaan kliinisesti tärkeitä elektrofysiologisia eroja pitkä QT-oireyhtymän eri alaryhmissä. Lisäksi havaittiin, että kaliumkanavien ja beeta-adrenergisten reseptorien yleiset variantit voivat toimia pitkä QT-oireyhtymän "muuntelijageeneinä", jotka saattavat jossain määrin vaikuttaa potilaiden rytmihäiriöalttiuteen

Electrocardiographic Consequences Of Electrical And Anatomical Remodeling In Diabetic And Obese Humans

Background. Diabetes and obesity are two major risk factors for cardiovascular disease. Both can cause changes due to cardiac sources in body-surface potentials: BSPs), that is, in electrocardiograms: ECGs). By identifying the major effects of diabetes and obesity on BSPs, we hope to reveal the electrical phenotype of diabetes in body-surface ECGs in the presence of obesity. Methods. A Bidomain Platform was constructed to link heart-surface transmembrane potentials: TMPs) and BSPs. The Forward-Problem Module of the platform calculates BSPs from a bidomain-model of myocyte TMPs and torso anatomy. The platform also contains a Cardio-myocyte TMP Estimation Module in which an innovative method, named regularized waveform identification: RWI), was developed. It is a new approach used to reconstruct the TMPs from BSPs, that is, solving the electrocardiographic inverse bidomain problem. Using normal TMPs, BSPs were simulated on obese torsos and compared to BSPs on a normal torso to determine ECG changes that might accompany certain obese habitus. BSPs on a normal torso were also simulated with both normal TMPs and TMPs whose duration was increased in a manner expected to occur in the diabetic. In addition, BSPs were measured, heart and torso models were found on two adult male subjects: one normal and one obese diabetic. BSPs and estimated TMPs in these subjects, found by using the RWI method, were compared to identify ECG changes that might be found in the obese diabetic in a clinical setting. Results. Forward-problem solutions found for obese heart-torso models with normal TMPs compared to normal had relative errors: RE) of 12, 30, and 68\% for 20\% left-ventricular hypertrophy, 16\% abdomen extension, and displaced heart, respectively. These results suggest that standard 12-lead ECG measurement could be significantly affected by the anatomical changes associated with obesity. Simulation results also showed diabetic electrical remodeling may have a strong impact on BSPs. An RE of 125\% was observed between normal and diabetic BSPs due to prolongation of recovery that might accompany diabetes. Energy reduction of BSPs was found in both simulated and measured BSPs with obesity. Although QT interval prolongation found in simulated BSPs was not seen in the ECGs recorded from the obese diabetic subject, QT dispersion(QTd) was found increased in diabetic in both simulated and measure ECGs. Obviously, no statistical conclusions can be reached with our limited data set, but the suggestive results call for further clinical observations. TMPs were estimated in realistic, normal heart-torso model simulations using the RWI method. REs of about 15\% were found for up to 10\% noise added to BSPs; and for errors in heart size of 10\% and heart location of $\pm 1$ cm, which were significant improvements over conventional regularization methods alone. Conclusions. In this study, we characterized electrical changes with diabetes and anatomical changes with obesity; then independently evaluated their influences on body surface potentials: BSPs). These results suggest that standard 12-lead ECG measurements could be strongly influenced by the anatomical changes associated with obesity. Body-surface maps and inverse solutions to the heart-surface that minimize volume-conductor effects are likely to be more useful in investigating the influence of diabetic electrical remodeling among obese diabetic patients. Simulation results showed that the RWI inverse solution performed much better than traditional regularization methods alone and is robust in the presence of noise and geometric error. By incorporating temporal information, in the form of the basic TMP wave shape, estimation accuracy was enhanced while maintaining computational simplicity

Electrophysiological and cellular analysis of filamin-C mutations causing cardiomyopathy using human iPSC-derived cardiomyocytes

Background: Arrhythmogenic Cardiomyopathy (AC) is a genetic cardiac disease resulting from different mutations within proteins constituting the intercalated disc, including desmosomal and nondesmosomal proteins. Recent studies have revealed that mutations in filamin-C (FLNC) may lead to AC. The arrhythmogenesis and electrophysiological effects of FLNC-related AC are incompletely understood. Therefore, the aim of this study is to assess the potential electrophysiological consequences of FLNC loss as occurs in AC in human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs). Specifically, I aimed to characterise abnormal electrical activity and the expression and function of key proteins in cardiac electrical activity such as gap junction protein connexin 43 (Cx43).// Methods: hiPSC-CMs were differentiated and observed by immunofluorescence microscopy. Small interfering RNA (siRNA) transfection was utilised to knockdown the expression of FLNC in hiPSC-CMs. Protein analysis was performed using western blotting to confirm the knockdown efficiency. Electrophysiological properties were recorded using a multielectrode array and manual patch clamping. Optical recording of membrane potential and calcium activity from hiPSC-CMs were also carried out using parameter sensitive dyes.// Results: Silencing of FLNC led to markedly decreased immunofluorescence signals of FLNC, Cx43, desmoplakin, and junctional plakoglobin. No significant reductions were noted in the immunofluorescence signals of voltage-gated sodium channel (Nav1.5) and plakophilin-2 compared with control hiPSC-CMs. Western blotting showed the reduction of FLNC and Cx43 expression following silencing of FLNC. Knockdown of FLNC resulted in disturbances to the recorded action and field potential signals of hiPSC-CMs and arrhythmic likeevents. Transfected hiPSC-CMs with siRNA-FLNC were associated with prolongation of calcium transient durations, optical action potential duration, and action potentials measured with patch clamping.// Conclusion: The current findings indicated that loss of FLNC resulted in a complex arrhythmogenic phenotype in hiPSC-CM