Update on Cardiac Arrhythmias in Patients with COVID-19

Pathophysiology of cardiac disease caused by SARS-CoV-2

SARS-CoV-2 is a single-stranded ribonucleic acid (RNA) virus enveloped with surface projections corresponding to spike glycoproteins (protein S) with two subunits, S1 and S2, which give it a crown-like appearance. S1 contains the binding domain receptor that will bind to the angiotensin-converting enzyme 2 (ACE2) peptidase, and S2 is responsible for membrane fusion. The first step in viral entry is binding the coronavirus S protein to the host's trimeric ACE2 protein.(10)

Angiotensin-converting enzyme II (ACE-2) is a membrane exopeptidase in type 2 pneumocytes, cardiomyocytes, pericytes, endothelium, and possibly other cell types.(2,10)

ACE2 is a multifunctional protein. Its primary function is the enzymatic conversion of angiotensin 2 (Ang II) to angiotensin (Ang)-(1-7) and Ang I to Ang-(1-9), which are cardiovascular protectors.

ACE2 plays a role in lung protection. Therefore, viral binding to this receptor dysregulates a lung protection pathway, contributing to viral pathogenicity.(11)

After endocytosis, the ACE2 surface is downregulated, accumulating angiotensin II, whose effects include increased inflammation, vasoconstriction, fibrosis, vascular permeability, and a propensity for thrombosis. Within the host cell's cytoplasm, RNA from the viral genome is released and replicated, leading to newly formed genomic RNA, which is processed into vesicles containing virions that fuse with the cell membrane to release the virus.(10)

SARS-CoV-2 infection is characterized by three phases:(12)

Phase 1 or early infection: characterized by anosmia, fever, dry cough, and constitutional symptoms as clinical manifestations, with biomarkers including lymphocytopenia, increased D-dimer levels, increased LDH levels, and increased cytokine levels.

Phase 2 or pulmonary: dyspnea and tachypnea are the clinical manifestations, and biomarkers include decreased O2 saturation, increased D-dimer levels, and pulmonary infiltrates (CT).

Phase 3 or severe hyperinflammation: clinical manifestations include acute respiratory distress syndrome (ARDS), septic shock, acute renal failure, acute heart failure, disseminated intravascular coagulation (DIC), and biomarkers include a significant decrease in O2 saturation, a greater increase in D-dimer, increased coagulation times, increased ferritin, increased interleukin 6 (IL-6), tumor necrosis factor α (TNFα), PCR, and increased troponin levels.

Severe cases of COVID-19 have been found to have very high levels of angiotensin II. Angiotensin II levels have been correlated with viral load due to ACE-2 inhibition by the virus.(2)

The pathophysiology of cardiovascular system disorders is not yet well defined, as many factors can alter it, such as the patient having a pre-existing heart condition, comorbidities (hypertension, diabetes, some degree of obesity, cancer) or use of medications such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or antivirals. However, it has been reported that, at the beginning of the interaction between the virus and the cells to be infected, transmembrane serine protease 2 (TMPRSS2) cleaves the S protein of the virus, causing its internalization by ACE2, induced by the S2 subunit. This first point could explain some manifestations because when ACE2 is damaged, it loses its regulatory function with angiotensin II, promoting increased blood pressure and a proinflammatory state, mainly affecting the lungs. In addition to endothelial dysfunction, there is activation of the innate immune system that causes cytokine storms, triggering an unbalanced response by type 1 and 28 T helper cells, causing damage to the microvascular system, hypoxemia, and activation of the coagulation system with inhibition of fibrinolysis. All these alterations lead to disseminated intravascular coagulation, which causes a general microcirculatory disorder contributing to myocardial cell damage and, subsequently, to a synergistic effect with other organic alterations in systemic failure.(1)

The research team suggests that the virus's pathogenicity, which causes complications in different organ systems, is due to the entry point, ACE II, found in the membranes of type 2 pneumocytes, cardiomyocytes, pericytes, endothelium, and possibly other cell types. The complications are due to the dysfunction of this protein, which causes increased blood pressure and a proinflammatory state.

Cardiac complications during COVID-19

Although patients with SARS-CoV-2 frequently present with respiratory symptoms, it is not unusual for clinical presentation to include symptoms that point to the cardiovascular sphere.

The most common forms of presentation are listed below.

Myocarditis

There is evidence of direct damage to the myocardium by coronavirus. One of the clinical presentations of COVID-19 can be chest pain, accompanied by alterations in the PR and ST segments on the electrocardiogram, with elevated blood biomarkers that suggest a diagnosis of myocarditis. Current evidence is insufficient to determine whether these patients preferentially present with preserved or reduced ejection fraction. The severity of the clinical picture will depend on the extent of myocardial damage and the levels of inflammatory mediators, such as interleukin 6 (IL-6). The outcome can be dramatic in those who develop fulminant myocarditis with cardiogenic shock.

Inciardi RM et al.(13) describe the case of a patient with no history of cardiovascular disease who was admitted for COVID-19 with dysfunction.

significant left ventricular enlargement, which had severe acute myopericarditis. SARS-CoV-2 infection causes focal or global myocardial inflammation, with necrosis areas that produce electrocardiographic and echocardiographic abnormalities and elevated myocardial damage markers that can be confused with acute coronary syndrome.(14)

Decompensated heart failure

Presentation as heart failure (HF) is common, affecting nearly 23 % of those infected with SARS-CoV-2. However, doubts remain as to whether it is more often due to an exacerbation of pre-existing disease or a de novo phenomenon secondary to myocarditis or stress cardiomyopathy.(7) Acute viral myocarditis, in this case caused by SARS-CoV-2, is not the only cause of acute heart failure, which can be severe. The enormous machinery of molecular and cellular mechanisms involved in the pathophysiology of COVID-19 in its most advanced stages explains why ventricular dysfunction occurs, regardless of the virus's direct involvement in the myocardium. The hypoxia caused by respiratory distress reduces the oxygen supply to the myocardium, which has increased demands for this gas due to sympathetic stimulation secondary to the infection. Furthermore, systemic inflammatory response syndrome promotes an increase in cytokines, which have a known depressant effect on the myocardium.(14)

Acute coronary syndrome

Patients with a history of ischemic heart disease or those at risk of atherosclerotic disease are at increased risk of developing ACS. Infection causes increased myocardial oxygen demand, usually linked to respiratory failure, which can trigger type II acute myocardial infarction secondary to an imbalance in oxygen supply/demand. On the other hand, the systemic inflammatory response can destabilize coronary atherosclerotic plaques, causing type I acute myocardial infarction.7Noria S et al 7 found that in a series of 19 patients with ST-elevation ACS and SARS-CoV-2 infection, there was wide variability in presentation, with a high prevalence of non-obstructive coronary artery disease and poor prognosis (72 % in-hospital mortality).

Thromboembolic events

The response to viral infection produces a state of hypercoagulability which, together with inflammation of the endothelial cells, can lead to platelet dysfunction and a predisposition to thrombus formation. Although these are more frequently venous, they can also occur in the arterial system and cause heart attacks at any level, as well as pulmonary thromboembolism and hypertension.(14)

Spiezia L et al15 found that the hypercoagulable state presented by COVID-19 patients is associated with an increase in fibrinogen levels with excessive fibrin polymerization secondary to infection; this virus promotes massive fibrin formation, which would explain the high levels of D-dimers, and this would not be associated with consumption coagulopathy. Patients infected with SARS-CoV-2 are at increased risk of venous thromboembolism, reaching 25 % in those admitted to the ICU. Antithrombin levels are lower in COVID-19 cases, and D-dimer and fibrinogen levels are higher than in the general population. In addition, the progression of disease severity is linked to a gradual increase in D-dimer. The maximum expression of this disorder is the presence of a coagulopathy similar to antiphospholipid syndrome or the establishment of disseminated intravascular coagulation.(2,7,14)

IL-6 plays an important role in the network of inflammatory mediators and can cause coagulation disorders through various pathways, such as hepatic stimulation for thrombopoietin and fibrinogen synthesis, increased expression of vascular endothelial growth factor, expression of monocyte tissue factors, and activation of the extrinsic coagulation system. The thrombin generated in turn can induce the vascular endothelium to produce more IL-6 and other cytokines. Cytokine storms and coagulation disorders thus feed back into each other.(2)

Based on the above, it is recommended that infected patients receive thromboprophylaxis, not only during hospitalization, but also for 45 days in individuals at high risk (reduced mobility, active cancer, elevated D-dimers).(7)

The research team suggests that the main cardiovascular complications caused by COVID-19 are due to damage to cardiomyocytes or dysfunction of another organ system, since myocarditis is due to damage to cardiomyocytes, causing elevated biomarkers. On the other hand, ACS is due to an imbalance in oxygen supply/demand due to respiratory system involvement or endothelial discontinuity. This leads to coagulation activation, causing prothrombotic events throughout the body.

Arrhythmias

Cardiac arrhythmias are another common manifestation in infected patients, with an approximate incidence of 16 %, which increases significantly with the severity of the disease (44 % in ICU patients). The presence of malignant arrhythmias such as ventricular tachycardia/fibrillation was reported in 5,9 % of cases. Myocardial injury, manifested by elevated troponin levels, has also been observed in these patients. Although the underlying mechanisms are still under investigation, they are attributed to hypoxia, metabolic alterations, and inflammatory and neurohumoral stress. Brugada-like electrocardiographic patterns have also been described, further complicating the correct differential diagnosis.(1,7)

Wang D et al.(16) found in their study that arrhythmias were present in 16,7 % of the patients studied and are one of the main complications during hospitalization. Although the type of arrhythmia or definition was not specified, its relationship (as well as acute myocardial damage) with admission to the ICU and older patient age was mentioned.

Three scenarios in which cardiac arrhythmias occur in COVID-19 are highlighted:(8)

1. Cardiac arrhythmias caused by COVID-19.

2. History of cardiac arrhythmias in patients with COVID-19.

3. Proarrhythmia secondary to COVID-19 treatment.

Cardiac arrhythmias caused by COVID-19

In patients with COVID-19, infection is a sufficient condition to cause cardiac arrhythmias in the absence of previous structural heart disease. Direct cardiac damage, myocarditis, myocardial ischemia, and heart failure are favorable scenarios for the development of atrial fibrillation (AF) and ventricular arrhythmias.(8)

The severe inflammatory reaction observed in some patients may, in theory, promote arrhythmias through sympathetic hyperactivity and the effect of interleukins (especially IL-6) on potassium channels and CYP3A4, which can lead to repolarization prolongation.(17)

The substrates, triggers, and modulators for the genesis and perpetuation of AF in this context are multiple, complex, overlapping, and difficult to control. Noteworthy are myocardial injury, hypoxia, ischemia, inflammation, hypokalemia and hypomagnesemia, metabolic acidosis, use of inotropic agents (dobutamine, dopamine, and norepinephrine), ventilator dyssynchrony, volume overload, increased sympathetic tone, and concomitant bacterial infection.(8)

No specific electrocardiographic changes have been described for COVID-19. Case reports have found a transient S1Q3T3 pattern and AV block, which have been explained by acute right ventricular overload and myocardial inflammation, respectively. ST elevation has also been reported, which has been linked to myocarditis. The limited information available is possibly associated with the difficulty of performing electrocardiograms in these patients due to the risk of spreading the infection through electrocardiographs and the risk to healthcare workers.(17)

The incidence of AF in patients with severe pneumonia, ARDS, and systemic inflammatory response syndrome is high. Ambrus et al.18 reported a 10 % incidence of recent-onset AF in critically ill patients with sepsis or ARDS.

History of cardiac arrhythmias in patients with COVID-19

Patients with hypertension, ischemic heart disease, cardiomyopathies, DM, obesity, and channelopathies constitute, per se, a high-risk subgroup for cardiac complications, which is increased in the context of COVID-19,(8) according to recent epidemiological studies. However, according to the literature reviewed, the magnitude of the association between cardiovascular comorbidity and the presence of symptoms at the time of diagnosis has not been determined in this type of patient.(19)

The comorbidities above are associated with a higher incidence of AF, atrial flutter (AFL), and VT.(8)

There are no data on what happens to baseline arrhythmias in patients with COVID-19. Given the relationship between atrial fibrillation (AF) and sepsis, events may be exacerbated. A study including 8 910 patients evaluated mortality and found, in a multivariate analysis, that a history of arrhythmias conferred a higher risk (OR 1,95, 95 % CI 1,33-2,86). However, there is also no information on the type of arrhythmia or the effect of each type on this risk.(17)

Similarly, in the face of severe infection and increased metabolic requirements, cases of ventricular arrhythmias may increase in patients with underlying heart disease.(17)

Pre-existing structural heart disease with scarring, fibrosis, and sutures creates areas with heterogeneous electrophysiological properties that determine the arrhythmogenic substrate. In critically ill patients, infection, hydroelectrolytic and acid-base disturbances, hypoxemia, ischemia, cytokine storm, and increased sympathetic nervous system tone are triggers and modulators of the preexisting arrhythmic substrate. Thus, a vicious circle is established; cardiac arrhythmias and their underlying conditions increase the risk of severe disease, while in the most severe forms, triggers and modulators of cardiac arrhythmias are more frequent.(8)

The existence of arrhythmias before COVID-19, regardless of whether they are atrial or ventricular in origin, poses a challenge in the management of patients. Comorbidity makes them vulnerable to developing severe forms of the disease with a poorer response to therapy. The most severe forms provide triggers and modulators of cardiac arrhythmias, and the prior use of antiarrhythmic drugs often limits protocol-based therapy and their interaction is potentially proarrhythmic.(8)

Proarrhythmia secondary to COVID-19 treatment

Proarrhythmia is defined as the generation of a new arrhythmia or the worsening of a pre-existing arrhythmia due to drugs used in doses considered non-toxic. It generally occurs in patients with structural heart disease; there is individual susceptibility, it is genetically determined, it is the result of abuse, misuse, or inherent to the drug, and it is often unpredictable.(8)

Many clinical trials are underway in patients with coronavirus disease 2019 (COVID-19) to test drugs that may be useful for its management. Some of these are associated with prolonged cardiac ventricular repolarization (evidenced on a conventional electrocardiogram as QT prolongation), which occurs due to alteration of various ion channels in the cell membrane of cardiac myocytes.(20)

The QT interval is the electrocardiographic representation of cardiac myocytes' depolarization and repolarization.(20)

The QT interval can be prolonged by multiple medications that directly or indirectly inhibit potassium ion channels (Ik). Inhibition of these channels will lead to an abnormal prolongation of phase 3 of the action potential, which is reflected electrocardiographically as T wave abnormalities or the appearance of the U wave. Prolongation of phase 3 may lead to early post-depolarizations due to the activation of calcium channels that allow calcium to enter the cell; the latter is what causes ventricular arrhythmias, mainly torsade de pointes.(20)

Prolongation of the QT interval predisposes to the onset of ventricular arrhythmias that can cause death. The arrhythmia most closely related to QT interval prolongation is torsade de pointes, which can rapidly degenerate into ventricular fibrillation. It is also important to mention that for every 10 ms of QT interval prolongation, the risk of torsades de pointes increases by 7 %.(20)

Some patients have ion channel abnormalities due to genetic mutations that cause pathological QT interval prolongation, a condition known as long QT syndrome. Currently, there are multiple types of this syndrome, and it is one of the hereditary conditions most frequently associated with sudden death. Great caution should be exercised with drugs prescribed to these patients, as they could further prolong the QT interval and precipitate malignant arrhythmias. At present, there are no reports of cases of long QT syndrome and COVID-19. Still, if any arise, great caution should be exercised with the drugs used.(20)

The appearance of early post-potentials has been demonstrated for drugs that prolong the QTc, hypokalemia, hypoxia, increased partial pressure of carbon dioxide, elevated catecholamine concentrations, and bradycardia and pauses. All of these conditions can occur in patients with COVID-19. Their confluence is associated with an increase in Na2+ or Ca2+-dependent inward currents, or with a decrease in K2+-dependent outward currents, which causes prolongation of the action potential and, in susceptible cases, generates post-potentials that trigger TdP.(8)

Pharmacological treatment protocols for SARS-CoV-2 include a combination of drugs that seek a synergistic effect. Despite limited evidence on the efficacy of many of these drugs, those believed to have an effect against the virus are being used. The drugs used are: chloroquine/hydroxychloroquine, protease inhibitors (lopinavir-ritonavir), remdesivir, azithromycin, interferon, glucocorticoids, and monoclonal antibodies (tocilizumab).(8)

The Cuban protocol defines six therapeutic scenarios. The first three are community population, traveler surveillance centers, and contact isolation centers; they apply prophylactic measures to administer prevengo vir and biomodulin T to vulnerable patients at higher risk. Patients in care centers for suspected cases are treated with oseltamivir, azithromycin, and interferon alfa 2b. Patients hospitalized in open wards are given Kaletra (lopinavir-ritonavir), chloroquine, and interferon alfa-2 b. In units for seriously and critically ill patients, they are treated with Kaletra, chloroquine, tocilizumab, erythropoietin, sulfacetamide, and plasma. These treatments are part of clinical trials, as there is currently no specific treatment for COVID-19.(8)

Chloroquine and its structural analogue, hydroxychloroquine, are antimalarial agents with therapeutic properties for connective tissue diseases such as systemic lupus erythematosus and rheumatoid arthritis. They also have powerful immunomodulatory effects, including the reduction of cytokines such as interleukin 1 and 6 (IL-1, IL-6), tumor necrosis factor (TNF), and interferon (IFN). In vitro activity has been demonstrated against RNA viruses (rabies, poliovirus, dengue, Ebola) and coronaviruses (SARS-CoV-1 and MERS-CoV) and is currently used for COVID-19 disease. Its antiviral effect occurs by limiting the binding of viral particles to the cell surface, preventing endocytosis, suppressing virus fusion with endosomes, and limiting the virus maturation process. Adverse events associated with its use include ventricular repolarization disorders (prolonged QT interval) with increased susceptibility to developing serious ventricular arrhythmias, such as torsade de pointes, ventricular fibrillation, and sudden death. This effect is dose-dependent and is due to the blockade of the KCNH2 potassium channel.(21)

A concern with the use of these drugs is that they can cause QTc prolongation, thereby increasing the possibility of TdP and sudden death. Another effect on the cardiovascular system that is of concern is the decrease in intracardiac conduction velocity, which becomes evident with conduction disorders of varying degrees. Adverse effects on the heart are rare and associated with long-term treatment; however, they should be monitored due to their implications regarding mortality.(8)

Therefore, it is advisable not to administer hydroxychloroquine if you have a baseline QTc > 550 ms. If QTc < 500 mg, with narrow QRS, reevaluate at the second and fourth doses of the medication. If 550 mg is exceeded, discontinue and consult a cardiologist (either at the second or fourth dose). If the QTc is not prolonged (value < 550 ms), treatment may be continued with daily monitoring of the QTc.(22)

Azithromycin is an antimicrobial belonging to the macrolide family. Its use in patients with COVID-19 is based on minimal evidence from a small study. Six patients in the hydroxychloroquine arm were also treated with azithromycin. A significant reduction in SARS-CoV-2 positivity in nasopharyngeal secretions was found compared with hydroxychloroquine alone. Macrolides are capable of prolonging the QT interval and inducing ventricular arrhythmias. It has been proposed that chronic exposure to azithromycin increases the current of Sodium (Na+), which promotes QT prolongation and cardiac arrhythmias. Azithromycin has been associated with QTc prolongation and TdP in isolated cases, mainly in individuals with additional risk factors.(21)

Kaletra (lopinavir-ritonavir) is a combination of protease inhibitors useful in the treatment of HIV infection. In vitro and animal activity against other coronaviruses, such as SARS and MERS, has been reported. In patients with severe COVID-19, it showed no additional benefit over standard treatment. No major proarrhythmic adverse events were reported in either arm of the study, and there was only one case of QTc prolongation in the lopinavir-ritonavir arm (no details on the degree or existence of other risk factors for concomitant QTc prolongation). Its use carries a moderate risk of affecting atrioventricular (AV) conduction, with reports of AV block and QTc prolongation, but a low risk of TdP when used alone.(21)

The risk of proarrhythmia from the use of these drugs is low when used individually; however, in the context of COVID-19, several of them are almost always included at the same time. In addition, special attention should be paid to patients undergoing treatment with antiarrhythmic drugs due to the risk of ventricular arrhythmias secondary to proarrhythmia, due to interaction with the drugs included in the COVID-19 treatment protocol.(8)

In the case of interferon alfa 2b, oseltamivir, tocilizumab, erythropoietin, and sulfacen, there is no evidence of reports of proarrhythmia, nor are there any theoretical elements regarding their mechanism of action that would justify their occurrence.(8)

The research team suggests that the causes of arrhythmias in COVID-19 are due to QT interval prolongation, which is caused by myocardial damage from the disease or exacerbated by it due to a previous history, or by the proarrhythmic effects of some drugs used in the treatment of this disease, hence the importance of monitoring and ECG control when starting and continuing treatment with these drugs.