Digital twinning of the human ventricular activation sequence to Clinical 12-lead ECGs and magnetic resonance imaging using realistic Purkinje networks for in silico clinical trials.

Cardiac in silico clinical trials can virtually assess the safety and efficacy of therapies using human-based modelling and simulation. These technologies can provide mechanistic explanations for clinically observed pathological behaviour. Designing virtual cohorts for in silico trials requires exploiting clinical data to capture the physiological variability in the human population. The clinical characterisation of ventricular activation and the Purkinje network is challenging, especially non-invasively. Our study aims to present a novel digital twinning pipeline that can efficiently generate and integrate Purkinje networks into human multiscale biventricular models based on subject-specific clinical 12-lead electrocardiogram and magnetic resonance recordings. Essential novel features of the pipeline are the human-based Purkinje network generation method, personalisation considering ECG R wave progression as well as QRS morphology, and translation from reduced-order Eikonal models to equivalent biophysically-detailed monodomain ones. We demonstrate ECG simulations in line with clinical data with clinical image-based multiscale models with Purkinje in four control subjects and two hypertrophic cardiomyopathy patients (simulated and clinical QRS complexes with Pearson's correlation coefficients > 0.7). Our methods also considered possible differences in the density of Purkinje myocardial junctions in the Eikonal-based inference as regional conduction velocities. These differences translated into regional coupling effects between Purkinje and myocardial models in the monodomain formulation. In summary, we demonstrate a digital twin pipeline enabling simulations yielding clinically consistent ECGs with clinical CMR image-based biventricular multiscale models, including personalised Purkinje in healthy and cardiac disease conditions.

Sex differences in the origin of Purkinje ectopy-initiated idiopathic ventricular fibrillation.

BACKGROUND: Purkinje ectopics (PurkEs) are major triggers of idiopathic ventricular fibrillation (VF). Identifying clinical factors associated with specific PurkE characteristics could yield insights into the mechanisms of Purkinje-mediated arrhythmogenicity. OBJECTIVE: The purpose of this study was to examine the associations of clinical, environmental, and genetic factors with PurkE origin in patients with PurkE-initiated idiopathic VF. METHODS: Consecutive patients with PurkE-initiated idiopathic VF from 4 arrhythmia referral centers were included. We evaluated demographic characteristics, medical history, clinical circumstances associated with index VF events, and electrophysiological characteristics of PurkEs. An electrophysiology study was performed in most patients to confirm the Purkinje origin. RESULTS: Eighty-three patients were included (mean age 38 ± 14 years; 44 [53%] women), of whom 32 had a history of syncope. Forty-four patients had VF at rest. PurkEs originated from the right ventricle (RV) in 41 patients (49%), from the left ventricle (LV) in 36 (44%), and from both ventricles in 6 (7%). Seasonal and circadian distributions of VF episodes were similar according to PurkE origin. The clinical characteristics of patients with RV vs LV PurkE origins were similar, except for sex. RV PurkEs were more frequent in men than in women (76% vs 24%), whereas LV and biventricular PurkEs were more frequent in women (81% vs 19% and 83% vs 17%, respectively) (P < .0001). CONCLUSION: PurkEs triggering idiopathic VF originate dominantly from the RV in men and from the LV or both ventricles in women, adding to other sex-related arrhythmias such as Brugada syndrome or long QT syndrome. Sex-based factors influencing Purkinje arrhythmogenicity warrant investigation.

Estimation of Personalized Minimal Purkinje Systems From Human Electro-Anatomical Maps.

The Purkinje system is a heart structure responsible for transmitting electrical impulses through the ventricles in a fast and coordinated way to trigger mechanical contraction. Estimating a patient-specific compatible Purkinje Network from an electro-anatomical map is a challenging task, that could help to improve models for electrophysiology simulations or provide aid in therapy planning, such as radiofrequency ablation. In this study, we present a methodology to inversely estimate a Purkinje network from a patient's electro-anatomical map. First, we carry out a simulation study to assess the accuracy of the method for different synthetic Purkinje network morphologies and myocardial junction densities. Second, we estimate the Purkinje network from a set of 28 electro-anatomical maps from patients, obtaining an optimal conduction velocity in the Purkinje network of 1.95 ± 0.25 m/s, together with the location of their Purkinje-myocardial junctions, and Purkinje network structure. Our results showed an average local activation time error of 6.8±2.2 ms in the endocardium. Finally, using the personalized Purkinje network, we obtained correlations higher than 0.85 between simulated and clinical 12-lead ECGs.

3D magnetization transfer (MT) for the visualization of cardiac free-running Purkinje fibers: an ex vivo proof of concept.

OBJECTIVES: We investigate the possibility to exploit high-field MRI to acquire 3D images of Purkinje network which plays a crucial role in cardiac function. Since Purkinje fibers (PF) have a distinct cellular structure and are surrounded by connective tissue, we investigated conventional contrast mechanisms along with the magnetization transfer (MT) imaging technique to improve image contrast between ventricular structures of differing macromolecular content. METHODS: Three fixed porcine ventricular samples were used with free-running PFs on the endocardium. T1, T2*, T2, and M0 were evaluated on 2D slices for each sample at 9.4 T. MT parameters were optimized using hard pulses with different amplitudes, offset frequencies and durations. The cardiac structure was assessed through 2D and 3D T1w images with isotropic resolutions of 150 µm. Histology, immunofluorescence, and qPCR were performed to analyze collagen contents of cardiac tissue and PF. RESULTS: An MT preparation module of 350 ms duration inserted into the sequence with a B1 = 10 µT and frequency offset = 3000 Hz showed the best contrast, approximately 0.4 between PFs and myocardium. Magnetization transfer ratio (MTR) appeared higher in the cardiac tissue (MTR = 44.7 ± 3.5%) than in the PFs (MTR = 25.2 ± 6.3%). DISCUSSION: MT significantly improves contrast between PFs and ventricular myocardium and appears promising for imaging the 3D architecture of the Purkinje network.

Idiopathic multifocal myocardial atrophy with fibrosis and fatty infiltration involving Purkinje fibres in a 13-year-old Arabian broodmare: Histopathological features.

Myocardial atrophy with fibrosis and fatty infiltration involving the cardiac conduction system is relatively unusual in horses. We herein report of such a case in a 13-year-old Arabian broodmare that had spontaneously died on a paddock. An autopsy revealed multifocal myocardial atrophy with concomitant fibrosis and fatty infiltration in both the ventricles and interventricular septum. The Purkinje fibres in the ventricles and interventricular septum were surrounded by thick fibrous or adipose tissues adjacent to atrophic myocardial cells. Myocardial fibrosis and fatty infiltration were likely secondary to myocardial atrophy, occurring as a pathological response triggered by the repair of muscular wall injury. However, there were no major vascular pathologies (e.g. atherosclerosis and arteriosclerosis); hence, the pathogenesis of myocardial atrophy was unclear. There was no evidence of myocardial atrophy ̵ induced pathologies such as infarct, ischaemic lesions, myocardial degeneration, myocarditis and endocarditis. However, such an unusual histopathological pattern may be associated with rapid clinical deterioration and death.

Longitudinal dissociation and transition in thickness of the His-Purkinje system cause various QRS waveforms of surface ECG under His bundle pacing: A simulation study based on clinical observations.

AIMS: His bundle pacing (HBP) is a feasible and reliable alternative to conventional right ventricular pacing (RVP), but associated ECG (electrocardiogram) changes have not been well-studied. This study aimed to determine the mechanisms underlying ECG changes associated with HBP using patient-specific multiscale heart simulations. METHODS: ECGs were recorded in two patients who were treated by HBP under a native rhythm and HBP at high and low voltages. We created patient-specific multiscale simulation heart models of these patients and performed ECG simulation under these conditions. Using these results and detailed information on the electrical field around the pacing lead, we investigated mechanisms underlying the observed ECG changes. RESULTS: Heart simulations successfully reproduced ECGs under a native rhythm for both cases. In case 1, nonselective HBP produced a left bundle branch (LBB) block pattern, which was reproduced as a selective right bundle branch (RBB) pacing. However, in case 2, ECG under nonselective HBP showed an RBB block pattern, which could not be reproduced by the commonly used framework. Findings on the electrical field and anatomy of the His bundle and its branches suggested that longitudinal dissociation of the His bundle and transition of thickness in the stem of the LBB caused a conduction delay in the RBB to produce these ECG changes in this patient. CONCLUSION: Variations in the anatomy of the His bundle and its branches may underlie the diverse ECG responses to HBP. These variations should be taken into account when performing this therapy.

A novel method to identify the origin of ventricular tachycardia from the left fascicular system.

BACKGROUND: There are well-described ablation strategies to treat left fascicular tachyarrhythmia (LFTA); however, a method to predict the origin is less well characterized. OBJECTIVE: The purpose of this study was to predict the origin of LFTAs by measuring the HV interval during normal sinus rhythm (NSR) and LFTAs. METHODS: A predicted value of the earliest presystolic potential (PP) time was calculated using the HV interval during NSR and LFTAs [(HVNSR+HVLFTA)/2]. The earliest retrograde PP was mapped during LFTAs, and the relationship between the predicted and the mapped value was correlated. RESULTS: Twenty-one consecutive patients with LFTAs were included in this study. Four patients (19%) had tachycardia originating from the left anterior fascicle; the mean HV interval was 50.3 ± 8.3 and 30.3 ± 11.6 ms during NSR and tachycardia, respectively. The mapped retrograde PP during LFTAs preceded the onset of the surface electrocardiogram by 34 ± 9.4 ms. Seventeen patients (81%) had tachycardia originating from the left posterior fascicle; the mean HV interval was 49.2 ± 4.6 and -4.5 ± 13.6 ms during NSR and LFTAs, respectively. Nineteen patients with successful ablation were analyzed; the mean HV interval was -0.9 ± 16.8 and 49.5 ± 4.6 ms during LFTAs and NSR, respectively. The predicted value was similar to the mapped value (24.4 ± 9.1 ms vs 25.2 ± 8.1 ms; P = .76). The predicted value was well correlated with that from the target site (r = 0.97; P < .001). CONCLUSION: The earliest retrograde PP site for the ablation of LFTAs can be predicted measuring the HV interval during NSR and LFTAs. Successful ablation can be performed during NSR for patients with LFTAs inducible at baseline but noninducible during mapping.

Ungulates heart model: a study of the Purkinje network using India ink injection, transparent specimens and computer tomography.

The Purkinje network is not macroscopically visible in human hearts. Sunao Tawara found himself in trouble in the early 1900s, when studying the human heart network. He gained a much better understanding of the net after starting to work with ungulates' hearts. The ungulate heart is proposed as an auxiliary didactic model for the study of the human conduction system. This work provides a detailed description of the India ink injection technique to allow a naked eye visualization of the Purkinje network. The heart muscle was made diaphanous for direct visualization of the ungulate heart intramyocardial network, and computer tomography was employed for visualization of the three dimensional structure of the whole network. The intramyocardial network in the interventricular septum was identified. The pattern of the Purkinje network is described as a connected noneulerian graph, and its possible implications on the mechanism of arrhythmias is discussed. The main differences between the ungulate and human heart conduction systems are stressed.

Parametrization strategies for matching activation sequences in models of ventricular electrophysiology.

Driven by recent advances in medical imaging, image segmentation and numerical techniques computer models of ventricular electrophysiology account for increasingly finer levels of anatomical and biophysical detail. However, considering the large number of model parameters involved parametrization poses a major challenge. A minimum requirement in combined experimental and modeling studies which aim at making specific predictions on a case by case basis is to achieve good agreement in activation and repolarization sequences between model and experiment or patient data. In this study we propose basic techniques which aide in determining bidomain parameters to match ventricular activation sequences. Two specific aspects will be considered. First, conduction velocity in the ventricles is orthotropic and varies in space. An iterative parametrization algorithm is implemented which determines appropriate conductivities which yield prescribed velocities. Secondly, impulse propagation in the ventricles is initiated subendocardially at Purkinje-ventricular junctions, the terminal endings of Purkinje system (PS), and, thus, the PS plays a key role in determining the shape of activation wave fronts as reflected in the QRS complex of the electro-cardiogram (ECG). While ventricular models equipped with generic PS topologies match well with experimental observation in terms of epicardial breakthrough sites, predicted ECGs match poorly with known key ECG characteristics.

Clinical evaluation of left ventricular moderator band in 12 dogs.

We retrospectively examined clinical data for 12 dogs in which echocardiography revealed the presence of left ventricular moderator bands (LMB). Physical examinations, electrocardiography and echocardiography revealed slight cardiac murmurs, increasing QRS complex and left ventricular turbulent flow (6 of the dogs), respectively. No differences were observed with respect to gender, and no specific clinical symptoms or types of dog that frequently develop this disorder were found.

Abnormal His-Purkinje system conduction leading to complete atrioventricular block in patients with hypertrophic cardiomyopathy: a report of 3 cases.

This case report describes three hypertrophic cardiomyopathy patients with abnormal His-Purkinje conduction and complete atrioventricular block with attacks of syncope and cardiopulmonary arrest. Although arrhythmias are common in hypertrophic cardiomyopathy, complete atrioventricular block is very rare. Prolonged QRS duration and abnormal His-Purkinje system conduction may result in complete atrioventricular block.

[Effect of propranolol on arrhythmia in individuals with false chordae in heart ventricles]. / Wplyw propranololu na zaburzenia rytmu u osób ze strunami rzekomymi w komorach serca.

In 4156 echocardiographic examinations, false chordae were observed in 91 persons (2.2%). It was shown that false chordae without evidence of traction caused no increase of the risk of development of ventricular arrhythmia (class II and over according to Lown). In 50% of persons with false chordae and the evidence of traction significant ventricular arrhythmia occurred. It was found that administration of the drugs with negative inotropic action may increase arrhythmia in persons with false chordae in the heart ventricles.

Echocardiographic features of left ventricular aneurysm and false tendon in a patient with postinfarction pseudoaneurysm after aneurysmectomy.

Three years after the repair of a true left ventricular aneurysm, a 62-year-old man was admitted to our department for spontaneous angina pectoris and heart failure. The two-dimensional echocardiogram revealed a uniformly dilated left ventricle with a large apical aneurysm, in which a thin, continuous, band-like echogenic structure, extending from the interventricular septum to the antero-lateral wall could be visualized. That structure was initially interpreted as a left ventricular false tendon. Color Doppler flow imaging, however, showed a continuous, phasic flow crossing the band-like structure. Thus, the diagnosis of a huge apical pseudoaneurysm was made and subsequently confirmed by angiographic findings. In conclusion, left ventricular pseudoaneurysms may present themselves with unusual morphologic features. In patients with equivocal two-dimensional echocardiographic findings, color Doppler flow imaging is helpful in clarifying morphologic ambiguities and in identifying unsuspected flow abnormalities.

[False chordae tendineae]. / Le false corde tendinee.

False tendons (FT) are fibrous or fibromuscular structures which cross the ventricular cavity with no connections with valvular leaflets. They were considered for a long time as normal structures but now cardiologists are interested because of the possible association with the so-called innocent murmur, and even more so for the role they can have in eliciting ventricular arrhythmias. Some Authors believe that arrhythmias can arise from the false tendons because they contain not only fibrous tissue but also muscular and conduction tissue. Arrhythmias can be triggered either by stretching of the Purkinje fibers or by distortion of the ventricular wall, where false tendons arise. At the same time they can act as reentry circuits due to their non-homogeneous structure. Due to the fact that false tendons may arise anywhere from the ventricular cavity, they have been classified according either to anatomic or echocardiographic criteria: the latter being more complex and difficult than the former for the difficulty in locating the attachment areas. In our echocardiographic laboratory we simply distinguish two types of false tendons: type I which parallel the interventricular septum or bridges from the postero-basal portion of the septum to the posterior left ventricular wall; type II which crosses the ventricular cavity more distally, towards the apex. In the anatomic studies the prevalence of the FT is rather homogeneous, ranging from 46 to 54.9%, while it is extremely variable in the echocardiographic studies, ranging from 0.2 to 71%. This is possibly due not only to the examiner's skills, or the equipment's quality but also to the population studied. Among the patients referred to our cardiac paediatric unit we have found false tendons in 80 (29.3%) out of 273 children without cardiac disease, age ranging from i day to 13 yrs. Males were affected twice more than females, 63.7% vs 36.3%.(ABSTRACT TRUNCATED AT 250 WORDS)