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  1. Current methods in electrocardiogram characterization
    Martis RJ, Acharya UR, Adeli H
    Comput Biol Med, 2014 May;48:133-49.
    PMID: 24681634 DOI: 10.1016/j.compbiomed.2014.02.012
    The Electrocardiogram (ECG) is the P-QRS-T wave depicting the cardiac activity of the heart. The subtle changes in the electric potential patterns of repolarization and depolarization are indicative of the disease afflicting the patient. These clinical time domain features of the ECG waveform can be used in cardiac health diagnosis. Due to the presence of noise and minute morphological parameter values, it is very difficult to identify the ECG classes accurately by the naked eye. Various computer aided cardiac diagnosis (CACD) systems, analysis methods, challenges addressed and the future of cardiovascular disease screening are reviewed in this paper. Methods developed for time domain, frequency transform domain, and time-frequency domain analysis, such as the wavelet transform, cannot by themselves represent the inherent distinguishing features accurately. Hence, nonlinear methods which can capture the small variations in the ECG signal and provide improved accuracy in the presence of noise are discussed in greater detail in this review. A CACD system exploiting these nonlinear features can help clinicians to diagnose cardiovascular disease more accurately.
    Matched MeSH terms: Arrhythmias, Cardiac/physiopathology
  2. Sodium channel haploinsufficiency and structural change in ventricular arrhythmogenesis
    Jeevaratnam K, Guzadhur L, Goh YM, Grace AA, Huang CL
    Acta Physiol (Oxf), 2016 Feb;216(2):186-202.
    PMID: 26284956 DOI: 10.1111/apha.12577
    Normal cardiac excitation involves orderly conduction of electrical activation and recovery dependent upon surface membrane, voltage-gated, sodium (Na(+) ) channel α-subunits (Nav 1.5). We summarize experimental studies of physiological and clinical consequences of loss-of-function Na(+) channel mutations. Of these conditions, Brugada syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated with sudden, often fatal, ventricular tachycardia (VT) or fibrillation. Mouse Scn5a(+/-) hearts replicate important clinical phenotypes modelling these human conditions. The arrhythmic phenotype is associated not only with the primary biophysical change but also with additional, anatomical abnormalities, in turn dependent upon age and sex, each themselves exerting arrhythmic effects. Available evidence suggests a unified binary scheme for the development of arrhythmia in both BrS and PCCD. Previous biophysical studies suggested that Nav 1.5 deficiency produces a background electrophysiological defect compromising conduction, thereby producing an arrhythmic substrate unmasked by flecainide or ajmaline challenge. More recent reports further suggest a progressive decline in conduction velocity and increase in its dispersion particularly in ageing male Nav 1.5 haploinsufficient compared to WT hearts. This appears to involve a selective appearance of slow conduction at the expense of rapidly conducting pathways with changes in their frequency distributions. These changes were related to increased cardiac fibrosis. It is thus the combination of the structural and biophysical changes both accentuating arrhythmic substrate that may produce arrhythmic tendency. This binary scheme explains the combined requirement for separate, biophysical and structural changes, particularly occurring in ageing Nav 1.5 haploinsufficient males in producing clinical arrhythmia.
    Matched MeSH terms: Arrhythmias, Cardiac/physiopathology*
  3. Fulltext The rationale and design of the Micra Transcatheter Pacing Study: safety and efficacy of a novel miniaturized pacemaker
    Ritter P, Duray GZ, Zhang S, Narasimhan C, Soejima K, Omar R, et al.
    Europace, 2015 May;17(5):807-13.
    PMID: 25855677 DOI: 10.1093/europace/euv026
    Recent advances in miniaturization technologies and battery chemistries have made it possible to develop a pacemaker small enough to implant within the heart while still aiming to provide similar battery longevity to conventional pacemakers. The Micra Transcatheter Pacing System is a miniaturized single-chamber pacemaker system that is delivered via catheter through the femoral vein. The pacemaker is implanted directly inside the right ventricle of the heart, eliminating the need for a device pocket and insertion of a pacing lead, thereby potentially avoiding some of the complications associated with traditional pacing systems.
    Matched MeSH terms: Arrhythmias, Cardiac/physiopathology
  4. A deep convolutional neural network model to classify heartbeats
    Acharya UR, Oh SL, Hagiwara Y, Tan JH, Adam M, Gertych A, et al.
    Comput Biol Med, 2017 10 01;89:389-396.
    PMID: 28869899 DOI: 10.1016/j.compbiomed.2017.08.022
    The electrocardiogram (ECG) is a standard test used to monitor the activity of the heart. Many cardiac abnormalities will be manifested in the ECG including arrhythmia which is a general term that refers to an abnormal heart rhythm. The basis of arrhythmia diagnosis is the identification of normal versus abnormal individual heart beats, and their correct classification into different diagnoses, based on ECG morphology. Heartbeats can be sub-divided into five categories namely non-ectopic, supraventricular ectopic, ventricular ectopic, fusion, and unknown beats. It is challenging and time-consuming to distinguish these heartbeats on ECG as these signals are typically corrupted by noise. We developed a 9-layer deep convolutional neural network (CNN) to automatically identify 5 different categories of heartbeats in ECG signals. Our experiment was conducted in original and noise attenuated sets of ECG signals derived from a publicly available database. This set was artificially augmented to even out the number of instances the 5 classes of heartbeats and filtered to remove high-frequency noise. The CNN was trained using the augmented data and achieved an accuracy of 94.03% and 93.47% in the diagnostic classification of heartbeats in original and noise free ECGs, respectively. When the CNN was trained with highly imbalanced data (original dataset), the accuracy of the CNN reduced to 89.07%% and 89.3% in noisy and noise-free ECGs. When properly trained, the proposed CNN model can serve as a tool for screening of ECG to quickly identify different types and frequency of arrhythmic heartbeats.
    Matched MeSH terms: Arrhythmias, Cardiac/physiopathology*
  5. Performance Evaluation of Time-Frequency Distributions for ECG Signal Analysis
    Hussein AF, Hashim SJ, Aziz AFA, Rokhani FZ, Adnan WAW
    J Med Syst, 2017 Nov 29;42(1):15.
    PMID: 29188389 DOI: 10.1007/s10916-017-0871-8
    The non-stationary and multi-frequency nature of biomedical signal activities makes the use of time-frequency distributions (TFDs) for analysis inevitable. Time-frequency analysis provides simultaneous interpretations in both time and frequency domain enabling comprehensive explanation, presentation and interpretation of electrocardiogram (ECG) signals. The diversity of TFDs and specific properties for each type show the need to determine the best TFD for ECG analysis. In this study, a performance evaluation of five TFDs in term of ECG abnormality detection is presented. The detection criteria based on extracted features from most important ECG signal components (QRS) to detect normal and abnormal cases. This is achieved by estimating its energy concentration magnitude using the TFDs. The TFDs analyse ECG signals in one-minute interval instead of conventional time domain approach that analyses based on beat or frame containing several beats. The MIT-BIH normal sinus rhythm ECG database total records of 18 long-term ECG sampled at 128 Hz have been analysed. The tested TFDs include Dual-Tree Wavelet Transform, Spectrogram, Pseudo Wigner-Ville, Choi-Williams, and Born-Jordan. Each record is divided into one-minute slots, which is not considered previously, and analysed. The sample periods (slots) are randomly selected ten minutes interval for each record. This result with 99.44% detection accuracy for 15,735 ECG beats shows that Choi-Williams distribution is most reliable to be used for heart problem detection especially in automated systems that provide continuous monitoring for long time duration.
    Matched MeSH terms: Arrhythmias, Cardiac/physiopathology
  6. Fulltext Effects of ageing on pro-arrhythmic ventricular phenotypes in incrementally paced murine Pgc-1β -/- hearts
    Ahmad S, Valli H, Edling CE, Grace AA, Jeevaratnam K, Huang CL
    Pflugers Arch., 2017 Dec;469(12):1579-1590.
    PMID: 28821956 DOI: 10.1007/s00424-017-2054-3
    A range of chronic clinical conditions accompany cardiomyocyte energetic dysfunction and constitute independent risk factors for cardiac arrhythmia. We investigated pro-arrhythmic and arrhythmic phenotypes in energetically deficient C57BL mice with genetic ablation of the mitochondrial promoter peroxisome proliferator-activated receptor-γ coactivator-1β (Pgc-1β), a known model of ventricular arrhythmia. Pro-arrhythmic and cellular action potential (AP) characteristics were compared in intact Langendorff-perfused hearts from young (12-16 week) and aged (> 52 week), wild-type (WT) and Pgc-1β -/- mice. Simultaneous electrocardiographic and intracellular microelectrode recordings were made through successive trains of 100 regular stimuli at progressively incremented heart rates. Aged Pgc-1β -/- hearts displayed an increased incidence of arrhythmia compared to other groups. Young and aged Pgc-1β -/- hearts showed higher incidences of alternans in both AP activation (maximum AP upshoot velocity (dV/dt)max and latency), recovery (action potential duration (APD90) and resting membrane potential (RMP) characteristics compared to WT hearts. This was particularly apparent at lower pacing frequencies. These findings accompanied reduced (dV/dt)max and increased AP latency values in the Pgc-1β -/- hearts. APs observed prior to termination of the protocol showed lower (dV/dt)max and longer AP latencies, but indistinguishable APD90 and RMPs in arrhythmic compared to those in non-arrhythmic hearts. APD restitution analysis showed that Pgc-1β -/- and WT hearts showed similar limiting gradients. However, Pgc-1β -/- hearts had shortened plateau AP wavelengths, particularly in aged Pgc-1β -/- hearts. Pgc-1β -/- hearts therefore show pro-arrhythmic instabilities attributable to altered AP conduction and activation rather than recovery characteristics.
    Matched MeSH terms: Arrhythmias, Cardiac/physiopathology
  7. Fulltext Multiple targets for flecainide action: implications for cardiac arrhythmogenesis
    Salvage SC, Chandrasekharan KH, Jeevaratnam K, Dulhunty AF, Thompson AJ, Jackson AP, et al.
    Br J Pharmacol, 2018 Apr;175(8):1260-1278.
    PMID: 28369767 DOI: 10.1111/bph.13807
    Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca2+ -mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro-arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Nav channel or intracellular ryanodine receptor (RyR2)-Ca2+ channel function. Flecainide accesses its transmembrane Nav 1.5 channel binding site during activated, open, states producing a use-dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak INa related to activation of Nav channels followed by rapid de-activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro-arrhythmic conditions reflecting loss of function of Nav 1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro-arrhythmic effects attributed to prolonged AP recovery by abnormal late INaL following gain-of-function modifications of Nav 1.5 channels in LQTS3 are reduced by flecainide. Anti-arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca2+ release could arise from its primary actions on Nav channels indirectly decreasing [Ca2+ ]i through a reduced [Na+ ]i and/or direct open-state RyR2-Ca2+ channel antagonism. The consequent [Ca2+ ]i alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Nav 1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na+ currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.

    LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

    Matched MeSH terms: Arrhythmias, Cardiac/physiopathology*
  8. Fulltext Ageing in Pgc-1β-/- mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology
    Edling CE, Fazmin IT, Chadda KR, Ahmad S, Valli H, Grace AA, et al.
    Biosci Rep, 2019 04 30;39(4).
    PMID: 30914453 DOI: 10.1042/BSR20190127
    Mice deficient in mitochondrial promoter peroxisome proliferator activated receptor-γ co-activator-1β (Pgc-1β-/- ) is a valuable model for metabolic diseases and has been found to present with several pathologies including ventricular arrhythmia. In the present study, our aim was to shed light on the molecular mechanisms behind the observed arrhythmic substrate by studying how the expression of selected genes critical for cardiac function differs in wild-type (WT) compared with Pgc-1β knockout mice and young compared with aged mice. We found that a clear majority of genes are down-regulated in the Pgc-1β-/- ventricular tissue compared with the WT. Although most individual genes are not significantly differentially expressed, a pattern is apparent when the genes are grouped according to their functional properties. Genes encoding proteins relating to ATPase activity, potassium ion channels relating to repolarisation and resting membrane potential, and genes encoding proteins in the cAMP pathway are found to be significantly down-regulated in the Pgc-1β deficient mice. On the contrary, the pacemaker channel genes Hcn3 and Hcn4 are up-regulated in subsets of the Pgc-1β deficient tissue. Furthermore, we found that with age, especially in the Pgc-1β-/- genotype, most genes are up-regulated including genes relating to the resting membrane potential, calcium homeostasis, the cAMP pathway, and most of the tested adrenoceptors. In conclusion, we here demonstrate how a complex pattern of many modest changes at gene level may explain major functional differences of the action potential related to ageing and mitochondrial dysfunction.
    Matched MeSH terms: Arrhythmias, Cardiac/physiopathology
  9. Fulltext Worldwide Survey of COVID-19-Associated Arrhythmias
    Coromilas EJ, Kochav S, Goldenthal I, Biviano A, Garan H, Goldbarg S, et al.
    Circ Arrhythm Electrophysiol, 2021 03;14(3):e009458.
    PMID: 33554620 DOI: 10.1161/CIRCEP.120.009458
    [Figure: see text].
    Matched MeSH terms: Arrhythmias, Cardiac/physiopathology
  10. Fulltext Pro-arrhythmic atrial phenotypes in incrementally paced murine Pgc1β-/- hearts: effects of age
    Valli H, Ahmad S, Fraser JA, Jeevaratnam K, Huang CL
    Exp Physiol, 2017 12 01;102(12):1619-1634.
    PMID: 28960529 DOI: 10.1113/EP086589
    NEW FINDINGS: What is the central question of this study? Can we experimentally replicate atrial pro-arrhythmic phenotypes associated with important chronic clinical conditions, including physical inactivity, obesity, diabetes mellitus and metabolic syndrome, compromising mitochondrial function, and clarify their electrophysiological basis? What is the main finding and its importance? Electrocardiographic and intracellular cardiomyocyte recording at progressively incremented pacing rates demonstrated age-dependent atrial arrhythmic phenotypes in Langendorff-perfused murine Pgc1β-/- hearts for the first time. We attributed these to compromised action potential conduction and excitation wavefronts, whilst excluding alterations in recovery properties or temporal electrophysiological instabilities, clarifying these pro-arrhythmic changes in chronic metabolic disease. Atrial arrhythmias, most commonly manifesting as atrial fibrillation, represent a major clinical problem. The incidence of atrial fibrillation increases with both age and conditions associated with energetic dysfunction. Atrial arrhythmic phenotypes were compared in young (12-16 week) and aged (>52 week) wild-type (WT) and peroxisome proliferative activated receptor, gamma, coactivator 1 beta (Ppargc1b)-deficient (Pgc1β-/- ) Langendorff-perfused hearts, previously used to model mitochondrial energetic disorder. Electrophysiological explorations were performed using simultaneous whole-heart ECG and intracellular atrial action potential (AP) recordings. Two stimulation protocols were used: an S1S2 protocol, which imposed extrasystolic stimuli at successively decremented intervals following regular pulse trains; and a regular pacing protocol at successively incremented frequencies. Aged Pgc1β-/- hearts showed greater atrial arrhythmogenicity, presenting as atrial tachycardia and ectopic activity. Maximal rates of AP depolarization (dV/dtmax ) were reduced in Pgc1β-/- hearts. Action potential latencies were increased by the Pgc1β-/- genotype, with an added interactive effect of age. In contrast, AP durations to 90% recovery (APD90 ) were shorter in Pgc1β-/- hearts despite similar atrial effective recovery periods amongst the different groups. These findings accompanied paradoxical decreases in the incidence and duration of alternans in the aged and Pgc1β-/- hearts. Limiting slopes of restitution curves of APD90 against diastolic interval were correspondingly reduced interactively by Pgc1β-/- genotype and age. In contrast, reduced AP wavelengths were associated with Pgc1β-/- genotype, both independently and interacting with age, through the basic cycle lengths explored, with the aged Pgc1β-/- hearts showing the shortest wavelengths. These findings thus implicate AP wavelength in possible mechanisms for the atrial arrhythmic changes reported here.
    Matched MeSH terms: Arrhythmias, Cardiac/physiopathology
  11. Fulltext Reduced cardiomyocyte Na+ current in the age-dependent murine Pgc-1β-/- model of ventricular arrhythmia
    Ahmad S, Valli H, Smyth R, Jiang AY, Jeevaratnam K, Matthews HR, et al.
    J Cell Physiol, 2019 Apr;234(4):3921-3932.
    PMID: 30146680 DOI: 10.1002/jcp.27183
    Peroxisome proliferator-activated receptor-γ coactivator-1 deficient (Pgc-1β-/- ) murine hearts model the increased, age-dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action potential (AP) upstroke rates and impaired conduction velocities potentially producing arrhythmic substrate. We tested a hypothesis implicating compromised Na+ current in these electrophysiological phenotypes by applying loose patch-clamp techniques in intact young and aged, wild-type (WT) and Pgc-1β-/- , ventricular cardiomyocyte preparations for the first time. This allowed conservation of their in vivo extracellular and intracellular conditions. Depolarising steps elicited typical voltage-dependent activating and inactivating inward Na+ currents with peak amplitudes increasing or decreasing with their respective activating or preceding inactivating voltage steps. Two-way analysis of variance associated Pgc-1β-/- genotype with independent reductions in maximum peak ventricular Na+ currents from -36.63 ± 2.14 (n = 20) and -35.43 ± 1.96 (n = 18; young and aged WT, respectively), to -29.06 ± 1.65 (n = 23) and -27.93 ± 1.63 (n = 20; young and aged Pgc-1β-/- , respectively) pA/μm2 (p 
    Matched MeSH terms: Arrhythmias, Cardiac/physiopathology
  12. Fulltext Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β-/-) murine hearts
    Ahmad S, Valli H, Chadda KR, Cranley J, Jeevaratnam K, Huang CL
    Mech Ageing Dev, 2018 Jul;173:92-103.
    PMID: 29763629 DOI: 10.1016/j.mad.2018.05.004
    INTRODUCTION: Ageing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors.

    MATERIALS AND METHODS: Pro-arrhythmic properties in electrocardiographic and intracellular recordings were compared in young and aged, peroxisome proliferator-activated receptor-γ coactivator-1β knockout (Pgc-1β-/-) and wild type (WT), Langendorff-perfused murine hearts, during regular and programmed stimulation (PES), comparing results by two-way ANOVA.

    RESULTS AND DISCUSSION: Young and aged Pgc-1β-/- showed higher frequencies and durations of arrhythmic episodes through wider PES coupling-interval ranges than WT. Both young and old, regularly-paced, Pgc-1β-/- hearts showed slowed maximum action potential (AP) upstrokes, (dV/dt)max (∼157 vs. 120-130 V s-1), prolonged AP latencies (by ∼20%) and shortened refractory periods (∼58 vs. 51 ms) but similar AP durations (∼50 ms at 90% recovery) compared to WT. However, Pgc-1β-/- genotype and age each influenced extrasystolic AP latencies during PES. Young and aged WT ventricles displayed distinct, but Pgc-1β-/- ventricles displayed similar dependences of AP latency upon (dV/dt)max resembling aged WT. They also independently increased myocardial fibrosis. AP wavelengths combining activation and recovery terms paralleled contrasting arrhythmic incidences in Pgc-1β-/- and WT hearts. Mitochondrial dysfunction thus causes pro-arrhythmic Pgc-1β-/- phenotypes by altering AP conduction through reducing (dV/dt)max and causing age-dependent fibrotic change.

    Matched MeSH terms: Arrhythmias, Cardiac/physiopathology
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