Drug-induced arrhythmia continues to be a major health issue worldwide. The need for reliable pro-arrhythmic predictors became relevant during early phases of the SarsCoV2 pandemic, when it was uncertain whether the use of hydroxychloroquine (HCQ) and azithromycin (AZM) could be more harmful than beneficial due to their reported pro-arrhythmic effects.In this work we describe a computational framework that employs a gender-specific, in-silico cardiac population to assess cardiac drug-induced QT-prolongation after the administration of a single or a combination of potentially cardiotoxic drugs as HCQ and AZM. This novel computational methodology is capable of reproducing the complex behavior of the clinical electrocardiographic response to drug-induced arrhythmic risk, in-silico. Using high performance computing, the computational framework allows the estimation of the arrhythmic risk in a population, given a variety of doses of one or more drugs in a timely manner and providing markers that can be directly related to the clinical scenario. The pro-arrhythmic behavior observed in subjects within the in-silico trial, was also compared to supplemental in-vitro experiments on a reanimated swine hearts. Evidence of transmurally heterogeneous action potential prolongation after the administration of a large dose of HCQ was an observed mechanism of arrhythmia, both in the in-vitro and the in-silico model. The virtual clinical trial also provided remarkably similar results to recent published clinical data. In conclusion, the in-silico clinical trial on the cardiac population is capable of reproducing and providing evidence of the normal phenotype variants that produce distinct arrhythmogenic outcomes after the administration of one or various drugs.

Human ventricular cardiac anatomy is extremely complex. Access to the ventricular chambers are often necessary for both mapping and treating ventricular arrhythmias. To date, electrophysiologists who perform these catheter ablations typically rely on fluoroscopy and the patient specific electroanatomical maps they generate so to begin to navigate through these complex functional anatomies. However, limited mapping resolutions do not provide often required insights relative to actual anatomical barriers. Hence, such discordances can lead to larger induced lesion sizes and ultimately, poorer patient outcomes. Here we describe both unique anatomic studies and the development of 3D computational models and assessment strategies for investigating human ventricular anatomies as they relate to arrhythmogenic mapping and therapies. A diverse range of fixed human anatomies were used to study and predict relative distances from an inter-chamber. placed balloon catheter to both true endocardial and epicardial surfaces. This work can be used to inform mapping and ablation catheter designs so to determine and optimize the placements of mapping electrodes to ensure both accurate electrical recording and applied ablations.

Electroanatomical mapping systems are being utilized clinically for locating arrhythmias within a given patient’s heart. Today, employed endocardial mapping systems are invasive and require extensive set-up time. Epicardial mapping systems, like CardioInsight™ from Medtronic, are non-invasive but require co-registration of electrodes to the heart, e.g. via a required Computed Tomography (CT) scan. This system has been used both clinically and in several laboratories in situ. The difficulties with in vitro uses are that the ex vivo perfused hearts lack an associated thoracic cavity, resulting in the possibility of inconsistent placement of electrodes, and poor conduction of epicardial signals. We are developing in our laboratory means to use the CardioInsight™ system on reanimated large mammalian hearts. Preliminary studies were conducted on swine hearts, but this system could be also be utilized with reanimated human hearts, making this research even more translatable. The use of this epicardial mapping system will allow for critical observations during pacing or ablation experiments and for collecting critical data for computational modeling.

Irreversible electroporation has regained a new popularity as a robust and effective ablation modality. One concern however that remains is the optimization of the several parameters to further implement the technology in medical therapies; one of the most important effects is the mitigation of muscle stimulation. Here we present the induced contractile force on swine skeletal muscle after delivery of irreversible electroporation therapies. We aim to evaluate two differing waveforms, the classic irreversible electroporation, IRE, with monophasic DC pulses of 100μs pulse widths, and a waveform of High Frequency Irreversible Electroporation, HFIRE. We observed that the short duration pulses of HFIRE, biphasic 2μs pulse width, effectively induced no contractile forces on skeletal muscle. In contrast IRE induced large contractions.

Cardiac myofiber structure and organizations play critical roles in the electrical and mechanical properties of the heart. Diffusion tensor magnetic resonance imaging (DTMRI) has been a useful imaging modality to visualize the myocardial fiber orientation with emerging clinical application. DTMRI takes advantage of the limited diffusion of water along the cardiac fiber’s longitudinal axis and provides the dominant direction of diffusion [1]. Until recently, DTMRI usage was relatively limited to clinical imaging of white matter within the brain. While there are limitations for cardiac use in vivo, due to tissue displacement and non‐rigid deformation, DTMRI is becoming a powerful diagnostic tool to assess structural heart damage. The data can also be the input into numerous computational simulations of the heart’s electrical activities. The Visible Heart®; Laboratories at the University of Minnesota, in collaboration with Lifesource, an organ procurement organization, maintains a large collection of human hearts that were donated for research. These organs are received fresh and subsequently preserved with 10% buffered formalin in the approximate end‐diastolic state for future anatomical studies. For the present studies, the hearts were rinsed of formalin and completely submerged in an agarose gel in attitudinally correct positions. The hearts are next scanned in a clinical 3T MRI scanner using a diffusion tensor sequence. The raw DTMRI DICOM files are then reconstructed using Diffusion Toolkit and visualized in TrackVis software [2]. This outputs a 3‐dimensional model that allows for visualization of the relative orientations of the myocardial fibers. Whole heart tissue models can also be generated using Materialise Mimics software from these scans. MRI scans of a heart from a 50 year old male with a history of myocardial infarction can be seen in Figure 1. The DTMRI axial images (Figure 1C) provide insights relative to the orientations of the myocardial fibers; which can then be transformed into a 3D diagram (Figure 1D) of directional eigenvectors. Future work will be done to improve resolutions by extending the number of averages acquired during such scanning. Increasing resolution will allow us to assess structural heart damage stemming from myocardial injuries: e.g. from ablations or due to myocardial infarction. Additionally, we hope to combine DTMRI with cardiac tissue models to create a 3D print that highlight regional myocardial fiber orientations. The fiber orientations from the DTMRI scans can also be incorporated into computer simulations, which may help elucidate the activation pathways of the heart. In some cases today, DTMRI can be utilized clinically to improve one’s understanding of the conduction system of the heart, which has implications in lead placement for pacing and ablation procedures. Researchers and clinicians can learn critical information relative to cardiac anatomy from DTMRI. An overview of the methods used to generate a 3D reconstruction of diffusion tensor MRI data. The resu...