Change in parameters for different conditions.
A high fidelity transmural anisotropic ventricular tissue model consisting of endocardial, mid myocardial, and epicardial myocytes were configured to investigate drug interaction, such as Hydroxychloroquine (HCQ), under hypoxia conditions without and with pro-arrhythmic comorbidity like hypokalemia in (a) ventricular tissue b) its arrhythmogenesis for different dosages and (b) two different pacing sequences (Normal and tachycardiac). In-silico ventricular modeling indicates HCQ has an insignificant effect on hypoxia with and without comorbidities, except in the combination of mild hypoxia with moderate hypokalemia condition and severe hypoxia with mild hypokalemia where it initiated a re-entrant arrhythmia. Secondly, incorporating drug dosage variations indicates the 10 μM HCQ created PVCs for all settings except in severe hypoxia conditions where re-entrant arrhythmia occurred. In addition to the dosage of HCQ utilized for treatment, the pacing protocol also influences the appearance of re-entrant arrhythmia only for severe hypoxia with 10 μM HCQ dosage alone. For all other conditions, including tachycardiac pacing protocol, no arrhythmia occurred. These findings infer that the arrhythmic fatality rate due to HCQ treatment for hypoxia can be effectively alleviated by subtly altering or personalizing the dosage of HCQ and aid in the treatment of hypoxia-induced symptoms caused by COVID.
- Ventricular Arrhythmia
- Transmural Tissue
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.  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 (), L-type calcium current () and rapid delayed rectifier potassium current (). Modeling of drug cardiotoxicity at the cellular level focuses predominantly on reducing current and leads to prolongation of APD in cells and QT interval in whole heart level, thereby leading to arrhythmias like TdP . However, a clinical study in France  reported that either HCQ alone or in combination with azithromycin is efficient in treating COVID-19. However, Sarkar et al., 2012  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.  shows the median baseline 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 prolongation of 500 ms or more, 13% had a change in 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) . He et al.,  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 . 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 . All these resulted in the liberal use of HCQ globally, in spite of contempt of paucity of evidence and adverse effect  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 . Further, this clinical study reported that different dosages of HCQ blocked the various ionic currents: , , and with different intensity. Based on the  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.
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:
The effect of COVID-19 infection on electrophysiological properties of ventricular tissue
Lack of clinical evidence that provides a detailed influence of HCQ on COVID-19 infected cardiac tissue. For example, changes in ECG, mechanism, and potential severity of ventricular arrhythmias like TdP
Mechanistic understanding of HCQ on ventricular tissues under comorbid scenarios, such as varying intensities of hypokalemia.
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.
2. Transmural cardiac tissue model
The 2D transmural section of the ventricular wall, is represented by an array of 250 × 100 cells, consisting of endocardial (endo), midmydocardial (M) and epicardial(epi) cells. The depolarisation and repolarisation patterns generated from the tissue are validated by simulating pseudo ECGs. The action potentials of different types of cardiomyocytes are described by the Ten Tusscher (TP06) model . A stimulus current of amplitude 52 A is applied for 1 ms is used to excite specific cell. The parameters of the model, tissue characteristics and integration scheme are adopted from Priya et al., 2017 . The change in cardiomyocyte’s ionic current parameters in the various configurations: hypokalemia and COVID-19 are summarized in Table 1.
|Mild COVID-19||5.5 mM|
|Severe COVID-19||5 mM|
As COVID-19 has been linked to causing hypoxemia , which in turn leads to hypoxia, this condition was included in the cardiac myocytes by increasing intracellular ATP concentration which would in turn lead to activation of an ATP sensitive potassium current. Using the formulation of Shaw and Rudy , ATP activated current is described by the following formula
where is the maximum conductance of current and has a value of 3.9 , H and n have a value of 2 and 0.24 respectively. The intracellular ATP concentration () under normal condition is 6.8 mM, but it decreases to 5.5 mM in mild hypoxia and 5 mM in severe hypoxia respectively. Similarly, is 0.042 for normal condition, 0.125 and 0.25 for mild and severe hypoxia respectively . Henceforth, in this study, hypoxia would be referred as COVID-19 condition. Further, reduction in the rapid delayed rectifying potassium current () and by 35% and 12% respectively in atrial cells as reported by  is adapted in our model.
To investigate the benefits and adverse effects of HCQ under control, COVID-19 and comorbid hypokalaemia, the ion channel variations corresponding to these conditions were included in the cells of the tissue one at a time, as reported by , the extracellular potassium concentration () is reduced by three stages: 85% as hypokalemia1 (mild), 55% as hypokalemia2 (moderate) and 45% as hypokalemia3 (severe). A regular pacing pulse of 800 ms (corresponding to 75 beats per minute) is applied in the tissue, and the corresponding voltage propagation is analyzed. Further, pseudo ECGs are generated for each of the clinical conditions. The variation in ECG, in particular the QT interval and T-wave morphology, both without and with HCQ and in presence of comorbidity is considered for analysis. Furthermore, the tissue is stimulated with premature stimuli in between the normal beats to study which conditions can initiate or sustain an arrhythmia.
3. Cardiac tissue mechanism(s) in control, COVID-19 and hypokalemia conditions, and with HCQ
To understand the spatiotemporal mechanism of the cardiac tissue, the lower leftmost corner (Cells 1:10,1:2) of the transmural tissue is stimulated. As a result of this stimuli, a convex wavefront propagates from the endo to mid and epi layer from the bottom to the top of the tissue. The repolarisation occurs first in the epi and endo layers, and M-cells in the mid layer are the last to repolarise. Normalized pseudo ECGs are synthesized from this tissue.
|Condition||QT interval (s)||T-peak (mV)|
|Mild COVID-19 with HCQ||0.340||0.181|
|Severe COVID-19 with HCQ||0.275||−0.153|
|Hypokalemia1 with HCQ||0.375||0.265|
|Hypokalemia2 with HCQ||0.410||0.255|
|Hypokalemia3 with HCQ||0.425||0.246|
|Hypokalemia1a and Mild COVID-19||0.335||0.127, 0.153|
|Hypokalemia1 and Mild COVID-19 with HCQ||0.350||0.186|
|Hypokalemia1 and Severe COVID-19||0.285||−0.16, −0.087|
|Hypokalemia1 and Severe COVID-19 with HCQ||0.285||−0.14|
|Hypokalemia2 and Mild COVID-19||0.355||0.141|
|Hypokalemia2 and Mild COVID-19 with HCQ||0.38||0.174|
|Hypokalemia2 and Severe COVID-19||0.300||−0.156|
|Hypokalemia2 and Severe COVID-19 with HCQ||0.305||−0.126|
|Hypokalemia3 and Mild COVID-19||0.365||0.133|
|Hypokalemia3 and Mild COVID-19 with HCQ||0.395||0.168|
|Hypokalemia3 and Severe COVID-19||0.31||−0.155|
|Hypokalemia3 and Severe COVID-19 with HCQ||0.32||−0.121|
In control conditions, a 0.345 sec QT interval and 0.2265 mV T-peak occurs. While in
Figure 1(ii-v) shows the pseudo ECGs generated for the different combinations of Hypokalemia and COVID-19 as well as in presence of HCQ. In comorbid hypokalemia1 condition as seen in Figure 1(ii), the QT interval increases by 2.89% (0.355 s), while the peak amplitude of T-wave increases only by 1.10% (0.229 mV), almost similar to control condition. When exposed to HCQ, the QT interval increases by 8.69% (0.375 ms) and T-peak amplitude increases by 16.99% (0.265 mV) in comparison to control. But, when infected by mild COVID-19, the QT interval decreases by 2.89% (0.335 s), yet a notched T-wave appears with the first T-peak of 0.127 mV and second peak of 0.153 mV is observed. On adding HCQ, the notched T-wave are replaced by positive T-waves. The QT interval is increased by 1.45% (0.350 mV) and T-peak is reduced by 17.88% (0.186 mV) in comparison with control. In contrast to control condition, pre-existing hypokalemia1 with severe COVID-19 reduces the QT interval by 17.39% (0.285 s) and a negative T-peak of 0.16 mV is observed i.e. suggestive of ischemia as seen in Figure 1(iii). HCQ drug does not have any noteworthy effect other than slight reduction of T-peak to −0.14 mV.
In hypokalemia2 in Figure 1(iv), the QT interval is prolonged by 10.14% (0.380 ms) but T-peak reduced by 4.19% (0.217 mV) is observed, and HCQ exposure increases 18.84% (0.410 ms) QT interval with 12.58% (0.255 mV) increase in T-peak. On considering hypokalemia2 and
Finally, in hypokalemia3, Figure 1(v), the QT interval is prolonged by 13.04% (0.390 ms) while the T-peak is reduced by 7.28% (0.210 mV), similar to hypokalemia2 observation. In HCQ presence, the QT interval increases by 23.18% (0.425 ms) and the T-peak increases by 8.61% (0.246 mV) comparing to control.
3.1 Arrhythmogenesis effect of HCQ on COVID-19 infected tissue including and excluding hypokalemia
3.1.1 Premature pacing sequence protocol
The scientific community has well accepted that early or late repolarization of the ventricular myocytes manifest due to ionic imbalances and are regulated by different mechanisms; which are involved in or responsible for various life-threatening cardiac diseases. Further, to understand the arrhythmia mechanism, cardiac tissue is paced with premature beats (PBs) in between the normal pacing beats of 800 ms. Three consecutive PBs (single or two PBs are not effective in creating an arrhythmia) are applied to strive in initiating an arrhythmic pattern. PBs duration is determined as the period the endo cell comes out of the refractory state and are re-excitable. The subsequent sections describe the possibility of occurrence of arrhythmia on pacing the tissue with PBs in
3.1.2 Arrhythmogenesis response for mild and severe COVID-19 cardiac tissue: when treated with HCQ
Figure 2 shows the pseudo-ECG on including
3.1.3 Arrhythmogenesis mechanism for the pre-existing Hypokalemia of COVID-19 cardiac tissue: when treated with HCQ
To investigate the impact of COVID-19, pseudo ECGs a shown in Figure 3 are generated on pacing the tissue with PBs in the presence of different degree of Hypokalemia, severity of COVID-19 and on including HCQ.
In Figure 3(ii), hypokalemia1 and
On adding HCQ and pacing the tissue with 3 PBs, each of 330 msec duration, in between the regular pacing interval of 800 msec, although arrhythmic-like activity is observed from 0.37 sec to 1.295 sec in the pseudo ECG, this is due to the depolarisation and repolarisation sequence of the cells in the tissue and not because of reentry. Normal beats are resumed from 1.6 sec.
In case of
Figure 3(viii) shows the pseudo ECG on including Hypokalemia3 and
4. Dosage effects in COVID-19 infected cardiac tissue: HCQ and with AZM
To understand the influence of different dosages of HCQ alone and in combination with AZM in the COVID-19 infected cardiac tissue, the cardiomyocyte’s ionic current parameters are varied based on the clinical study reported by Wang et al., , and listed in Table 3. To the best of the author’s knowledge, prior art studies have not considered the role of temperature (fever) arising due to COVID-19; in this study, we configure the computational model of the ventricular tissue with an elevated temperature of 313.15 Kelvin.
|Current||HCQ (1 M)||HCQ (10 M)||HCQ (100 M)|
|HCQ (1 M) and AZM||HCQ (10 M) and AZM||HCQ (100 M) and AZM|
The ECG parameters, namely QT interval, T-peak and QRS duration are extracted from the pseudo ECG and tabulated in Table 4. Here, the cardiac tissue is paced with three consecutive premature beats (PBs) with a regular pacing interval of 800 ms (75 bpm). Initialization of the first PB in each case is determined as the endo cell’s period comes out of the refractory state and re-excitable. The consecutive beats get reduced by 10 msec. We further extended it in the presence of PBs in
|Dosage (μM)||Medication||Disease Condition||QT interval (sec)||T peak (mV)||QRS duration (sec)|
|1||HCQ with AZM||Control||0.375||0.24||0.070|
|1||HCQ with AZM||0.350||0.151||0.070|
|1||HCQ with AZM||0.285||−0.194||0.065|
|10||HCQ with AZM||Control||0.420||0.319||0.070|
|10||HCQ with AZM||0.390||0.227||0.070|
|10||HCQ with AZM||0.300||−0.119||0.065|
|100||HCQ with AZM||Control||0.630||0.317||0.075|
|100||HCQ with AZM||0.555||0.220||0.075|
|100||HCQ with AZM||0.355||−0.05||0.070|
In the control ventricular condition, the QT interval is observed to be 0.350 sec, T-peak is 0.232 mV and the QRS duration is 0.07 sec. In the case of adding 1 M, 10 M, and 100 M HCQ, the QT interval increases by 1.42%, 11.43%, and 44.28%, respectively, as shown in Figure 1(i). However, the T-peak decreases by 10.35% and 0.85% under 1 M and 100 M HCQ, but, in 10 M, it increases by 18.10%. Also, QRS duration increased by 7.14% in both 1 M and 10 M HCQ and by 21.4% in 100 M HCQ. Application of PBs in the 1 M HCQ or 10 M HCQ configuration, it gives rise to premature ventricular complexes (PVCs), as seen in Figure 1(ii) and the regular pacing sequence resumes at 2.4 sec. The appearance of PVC is due to the change in the repolarisation sequence with endo and mid cells repolarising first, followed by the epi cells. For the 100 M HCQ config, the three PBs gives rise to similar ECG complexes (with positive widened T-waves) as that in usual pacing. The regular beat resumes after a long pause at 3.3 sec.
Further, on the inclusion of 1 M AZM with each of the 1 M, 10 M and 100 M HCQ config, the QT interval prolongs by 7.14%, 20% and 80% respectively, in the control ventricle as shown in Figure 1(iii). Likewise, the T-peak increases by 3.87%, 37.5% and 36.63% under AZM in combination with 1 M, 10 M and 100 M HCQ respectively. However, the QRS duration remains the same in both 1M and 10 M HCQ, but increases by 7.14% in 100 M HCQ. Additionally, PVCs arise due to the inclusion of PBs in the combination of 1 M HCQ and AZM, and regular pulses resume at 1.6 sec. The occurrence of PVCs increases in the presence of PBs in 10 M HCQ, as seen in Figure 1(iv). This effect is due to the change in repolarisation sequence of the cells, specifically occurring from endo to mid and epi. Regular pulses resume at 2.4 sec. Although no reentry is generated in the tissue, the appearance of PVCs is a precursor to the development of arrhythmia. This finding is in line with the Wang et al., , where a dosage of 10 M HCQ prolonged the APD of cells but did not induce an arrhythmia in tissue on decreasing the pacing interval. Further, the combination of HCQ and AZM created arrhythmic activity. Although no arrhythmic event was generated in the presence of 100 M HCQ, widened T-waves occurred. Such broad-based and symmetrical T-waves, usually with increased amplitude, are termed as hyperacute T-waves and often associated with a depressed ST are a sign of acute ischemia (Figure 5) .
In the mild COVID-19 scenario, the QT interval becomes shortened by 7.14% (0.325 sec), and the T-peak decreases by 34.48% while the QRS duration remains unchanged as shown in (Figure 6(i)). While using 1 M HCQ, the model’s outcome, Pseudo ECG’s QT interval increases by 1.43% with a double notch T-peak of 0.124 mV and 0.110 mV. For the 10 M, the pseudo-ECG prolongs the QT interval and increases the T-peak by 11.42% and 18.10%, respectively. When HCQ dosage is 100 M, the QT interval raises by 35.71% with a 3.02% T-peak increase and 21.4% prolongation of QRS duration. However, in the case of 1 M and 10 M HCQ, QRS duration increases by 7.14%. In the arrhythmogenesis test, three reduced duration PBs are applied; when the first PB is applied; the mid and epi cells in the tissue start to repolarization due to the excitation from the previous beat, as a consequence, the wave propagates upward along with the endo and mid-layers, and lastly, it enters the epi layer of the cardiac tissue. Succeeding that, the wavefront repolarizes from the endo, mid and epi layer with the cells located at the top of the epi layer repolarizing last, resulting in an inverted T-wave. During the second PB excitation (0.8 sec), the wavefront depolarizes the endo and mid-layer but is not able to excite the epi layer cells as they are in a refractory state and this results in an ST-segment elevation in the ECG, as indicated in (Figure 6(ii). For the last PB, yet another PVC occurs and then regular beats resume at 1.6 sec. In the case of 10 M HCQ, due to the change in repolarization pattern, PVCs occur, yet they do not lead to the formation of re-entrant patterns. When PB’s are applied in 100 M HCQ setup, ECG complexes with widened T-waves are observed.
When AZM was supplemented with 1 M HCQ, 10 M HCQ and 100 M HCQ, the QT interval prolongs by a percentage of 7.14, 18.57 and 65.71 respectively, under
On including AZM, as indicated in Figure 6(vii), the QT interval increases by 2.85%, 7.14% and 22.85% with 1 M HCQ, 10 M HCQ and 100 M HCQ respectively in comparison to
5. Pacing sequence influence on arrhythmogenesis
In addition, to earlier pacing sequence, after the first beat is introduced, PBs are injected, under two condition, a) three unequal PBs with 800 msec (i.e., HR is 75 beats/min) pulse sequence, b) three equal PBs with 600 msec (i.e., HR is 100 beats/min), tachycardia pulse sequence. In each case, the first PBs duration is determined based on the refractory state and re-excitable property of bottom endo cells in the tissue. Further, the presence of PBs in mild and severe COVID-19 configurations for various HCQ dosages is applied to examine when an arrhythmia occurs.
Under mild COVID-19 and 1 M HCQ conditions, three PBs are injected with reduced duration after the first regular beat. The mid and epi cells are still repolarizing when the first PB is applied; this causes the depolarization wave to travel upwards and the endo and mid-layers and later enter the epi layer. Following depolarization, repolarization occurs in the endo, mid and then epi layer, with the cells located at the top of the epi layer repolarizing lastly, leading to a premature ventricular complex (PVC). The depolarization wavefront from the second PB at 0.8-sec proceeds along with the endo and mid layer, however, it cannot excite the epi layer cells as they are in a refractory state, and this appears as an ST-segment elevation. Further, the third PB gives rise to another PVC and at 1.6 sec, the regular beats resume with notched T-waves. For 10 M HCQ and mild cases, the three PBs give rise to PVCs due to the change in repolarization pattern, and wavefront reentry is absent. However, the QT interval and T-peak increase compared to control. ECG complexes with widened T-waves increased QT interval, and QRS duration is observed on pacing the tissue with three PBs under mild COVID-19 and 100 M HCQ conditions. In severe COVID-19, the inclusion of 1 M HCQ or 10 M HCQ with three PBs for every 245 msec and 265 msec respectively give rise to PVCs with an increased negative/inverted T-peak. This result could be due to the repolarization pattern changes. However, in 100 M HCQ conditions, no significant change is observed with similar ECG complexes occurring on applying three PBs at a pacing interval of 460 msec. The normal ECGs resumed at 1.2 sec in all three scenarios. Thus, the result inferred that an inverted T-wave morphology (representative of ischemia) could serve as a biomarker for severe COVID-19 conditions.
In this study, we considered a 2D anisotropic transmural ventricular model, in which the entire mid-layer is composed of M-cells with longer APD. However, certain studies have disputed the presence of M-cells [26, 27] and others have debated that they form islands in the endo-mid interface [28, 29]. Here, arrhythmic patterns are generated through a premature pacing sequence. Like other few other studies, , here we had not considered using the cross-pacing sequence to simulate an arrhythmia, as the propagation pattern would then travel parallel along the entire length of the ventricle from endo, mid and epi, and it would not mimic the actual depolarisation pattern in the ventricle and thereby result in irregular pseudo-ECG wave. Another option is the generic Short-long-short (SLS) pacing sequences that can initiate TdP pattern , which is our future direction. In clinical ECG recordings, self-terminating re-entrant arrhythmia of few cycles may not be considered critical. However, the limited duration of the reentry generated here is due to the consideration of the 2D ventricle model. In a three-dimensional or whole heart model, sustainable ventricular arrhythmias may occur. Finally, we considered 1 M, 10 M, and 100 M of HCQ and 1 M AZM dosage due to the ionic current percentage variation reported by Wang et al., clinical study.
This study presents the first complete electrophysiological mechanism of COVID infected ventricle tissue with and without hypokalemia comorbidities and its responses to HCQ treatment. This model strategically allows more direct studies of ion channel perturbation from clinical observation of infected victims. This study’s main conclusion is that when healthy cardiac tissue is infected by COVID, it engenders shorter QT interval, low amplitude or inverted T-waves and ST depression, which could be used as biomarkers. When treated with HCQ, in case of severe COVID-19, there is no significant adverse effect, but in mild COVID-19, QT interval prolongs and T-peak increases in ECG. Secondly, COVID-19 withal to the comorbid cardiac ventricle causes a slight QT interval elongation, notched T-waves in hypokalemia1, inverted T-waves in the presence of all severe hypoxia. In particular, the hypokalemic ventricle is prone to arrhythmia in the presence of COVID-19 and the addition of HCQ drug has no significant effects. Increasing the dosage of HCQ has the effect of prolonging the QT interval, and QRS duration and inclusion of AZM magnifies this effect. PVCs could be detected on pacing the tissue with PBs at lower doses of HCQ, and it led to the initiation of reentrant arrhythmia in
Conflict of interest
The authors declare no conflict of interest.
Sodium Current Rapid delayed rectifier potassium Current Slow delayed rectifier potassium Current Inward rectifier potassium Current L-type Calcium Current
Rapid delayed rectifier potassium Current
Slow delayed rectifier potassium Current
Inward rectifier potassium Current
L-type Calcium Current
Angiotensin-Converting Enzyme 2
Action Potential Duration
Premature Ventricular Complex
Severe Acute Respiratory Syndrome Coronavirus
Food and Drugs Administration
World Health Organization
Torsades de Pointes