**1. Introduction**

Precision medicine is significantly focused and promoted due to the development of next-generation sequencing, which implies high throughput and lower cost. Even though molecular and cell biology has improved basic understanding of many diseases, novel and pandemic diseases like Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) have many unanswered questions on infection

mechanism, progression, and impact of symptom-based treatment using "off label" drugs. For instance, Hydroxychloroquine (HCQ), an antimalarial drug widely used to boost the immune system, was attempted or explored towards treating COVID-19. The US Food and Drugs Administration (FDA) and WHO initially approved HCQ as an emergency medicine based on laboratory and clinical studies data. Irrespective of earlier findings suggesting that long-term (over 5 years) intake of HCQ is likely to contribute to the development of retinopathy, include QRS widening, QT interval prolongation, ventricular arrhythmias like Torsades de pointes (TdP), hypokalemia and hypotension [1, 2], in-vitro studies reported the potential activity of HCQ on SARS-CoV-2 [3, 4]. On a positive note, in experiments performed on mouse atria, Capel et al. [5] reported that HCQ acted as a bradycardiac agent (reducing the spontaneous beating rate) in sinoatrial cells via a dose-dependent reduction of multiple ionic currents: 'funny' current (*I <sup>f</sup>* ), L-type calcium current (*ICaL*) and rapid delayed rectifier potassium current (*IKr*). Modeling of drug cardiotoxicity at the cellular level focuses predominantly on reducing *IKr* current and leads to prolongation of APD in cells and QT interval in whole heart level, thereby leading to arrhythmias like TdP [6]. However, a clinical study in France [7] reported that either HCQ alone or in combination with azithromycin is efficient in treating COVID-19. However, Sarkar et al., 2012 [8] reported that one population of cell differs from another (i.e healthy vs. diseased) and electrophysiological variability manifests at each level, from molecular, cellular, organ, and organism level. Hence, considering the outcome of previous clinical evidence of HCQ on normal cells may be inadequate to provide the exact impact of the effect of HCQ on virus infected cells or tissue. As our particular interest is in the human cardiac system; specifically electrophysiology, we wish to emphasis the variability of COVID-19 in cardiac system. Clinical observations reported by Mercuro et al. [9] shows the median baseline *QTc* was 455 ms in 90 COVID-19 patients and in presence of HCQ, it increased to 473 ms. Among those who received HCQ alone, 19% had *QTc* prolongation of 500 ms or more, 13% had a change in *QTc* of 60 ms or more and 1 case of Torsade de Pointes (TdP) was reported. Thus it's very evident that investigating and understanding the cardiac manifestation

mechanism due to medication like HCQ drug is critical. Li X et al.'s study in 2019 on 175 patients with COVID-19 reported that, 39 patients had severe hypokalemia (under 3 mmol/L), 69 had moderate hypokalemia (3–3.5 mmol/L) and 67 were normokalemia (over 3.5 mmol/L) [10]. He et al., [11] proposed that ACE-2 signaling pathways may play a role in cardiac injury while hypoxemia caused by COVID-19 may cause damage to myocardial cells. Severe hypoxemia occurring in lungs of COVID-19 patients has been linked to loss of lung perfusion regulation and hypoxic vasoconstriction [12]. Acute viral infections like that of COVID-19 have been known to cause type 1 or 2 myocardial infarction though the frequency of STE in these patients is unclear [13]. All these resulted in the liberal use of HCQ globally, in spite of contempt of paucity of evidence and adverse effect [3] for a short span of time.

During this situation, Wang et al. reported that treating COVID-19 with a combination of HCQ and AZM elicited electrical alternates, re-entrant circuits and the wave breaks [14]. Further, this clinical study reported that different dosages of HCQ blocked the various ionic currents: *INa*, *ICaL*, *IKr* and *IK*<sup>1</sup> with different intensity. Based on the [15] finding, HCQ treatment for COVID-19 lead to ventricular arrhythmia and death in hospitalized COVID patients, In May 2020, WHO suspended the emergency usage of HCQ; later, this study article was retracted due to reporting of fabricated data. There is no clinical evidence that provides the detailed mechanism of HCQ's safety or adversity, particularly the cardiac cell and tissue, i.e., under what scenarios the target drug interaction may cause arrhythmias in patients.

*A High Fidelity Transmural Anisotropic Ventricular Tissue Model Function to Investigate… DOI: http://dx.doi.org/10.5772/intechopen.99873*

Although various researchers have attempted to study the pharmacokinetics of HCQ: it's the inhibitory mechanism on human cells under normal conditions and various abnormal pathologies, for the reasons noted, it is critical to zero down the effect of a drug and explains its response range. Such comprehensive study, either using in-vivo or clinical studies, is difficult in a short period with present-day technology. In this situation, computational models can help to elucidate and overcome the following aspects:


To address the above gaps, we develop a 2D transmural anisotropic ventricular tissue model framework that can help in primarily understanding the COVID-19 effect on the ventricular tissue, including the response to pharmacological agents like HCQ. Two variations of COVID-19; mild and severe infection are explored. Secondly, different levels of hypokalemia (mild, moderate and severe) along with COVID-19 are introduced one at a time to understand its effect on ventricular tissue In each case, the variations in the QT interval and T-peak are recorded. Finally, the tissue is excited with premature stimuli to analyze under which of the above three conditions the tissue becomes pro- arrhythmic. Although studies have established that HCQ induces QT prolongation, TdP arises only in certain scenarios. This study is an attempt to address the possibilities under which an arrhythmia is generated at the tissue level in presence of the above mentioned conditions.
