Potential Mechanisms of Ventricular Tachycardia/Ventricular Fibrillation Storm in COVID-19
SARS CoV-2 infection predominantly affects the respiratory system but has been causally linked to acute myocardial injury manifesting as elevated cardiac markers, namely troponin I and T [3, 4]. Several factors can cause myocardial injury following SARS CoV-2 infection, including type 1 myocardial infarction due to plaque rupture, type 2 myocardial infarction due to increased oxygen demand or reduced supply, myocarditis due to direct viral cytopathic effects, or indirect effects of systemic infection or cytokine storm in a hyper-inflammatory state resulting in stress cardiomyopathy [1, 2, 5, 6]. Additionally, patients with hyperglycemia are noted to have a significantly higher levels of inflammatory cytokines that blunt the effects of anti-inflammatory therapy. [7] The predominant mechanisms suspected to be involved in inducing VT/VF storm in the 2 cases reported are myocarditis, systemic inflammation, hemodynamic instability and hyperadrenergic state, hypoxia and acidosis, and use of proarrhythmic drugs. The demographic data and pertinent medical history are shown in table 1. Mechanisms responsible for the VT/VF storm pertaining to the 2 cases are discussed below (Figure 3).
Myocarditis
Myocarditis is the predominant mechanism of VT/VF storm in this patient cohort, which is marked by elevated cardiac high-sensitivity troponin levels as noted in both the cases described. Myocarditis due to SARS CoV-2 infection is not generally associated with pathognomonic findings on an electrocardiogram and often times the common presenting symptoms of fever, chest pain and palpitations maybe absent or obscured thus making clinical diagnosis difficult. Two large scale studies have reported acute myocarditis as the cause of SARS CoV-2-induced myocardial injury. A cardiac autopsy study of 39 confirmed COVID-19 cases proved cardiac infection by documenting the viral genome in myocardial tissue of 60% of patients [8]. Another study identified the SARS CoV-2 genome in 5 out of 104 endomyocardial biopsy samples with histological assessment revealing myocarditis, necrosis, and granulation tissue [9]. COVID-19-related myocarditis has been documented in several other studies, however, only few studies have demonstrated association between myocarditis and VT/VF storm in the setting of COVID-19 related myocarditis [10-14]. Tachyarrhythmias particularly non-sustained VT have been documented to be related to severity of acute illness and level of troponin elevation and found to be an independent factor of in-hospital mortality [15]. Additionally, SARS-CoV-2 related fulminant myocarditis is now a major consideration in patients who present with chest pain, elevated cardiac troponins and arrythmias with hemodynamic instability and left ventricular dysfunction on imaging [16]. These findings suggest early measurement of cardiac biomarkers in COVID-19 may help identify patients at risk of poor clinical outcome as reflected by the mortality of case 2 in our cohort (Table 2) [16].
Systemic Inflammation
Another possible mechanism responsible for ventricular arrythmia in our patient cohort is cytokine-mediated myocardial dysfunction, which can promote VT/VF storm in severe COVID-19 cases. The presence of inflammatory cytokines, i.e., interleukin-1, interleukin-6, and high-sensitivity C-reactive protein, has been associated with electrical storm in ICD implanted patients in previous studies [17]. Additionally, numerous case studies have documented an association between VT/VF storm and increased inflammatory markers like C-reactive protein in COVID-19 patients, which resolved with the resolution of inflammatory status [18, 19]. The mechanism by which inflammatory cytokines like tumor necrosis factor, interleukin-1, and interleukin-6 propagate arrhythmia involves altering function of cardiac ion channels also known as inflammatory cardiac channelopathy. These cytokines specifically alter the function of gap junctions, outward K+ currents, and L-type Ca2+ channels in the atrial and ventricular myocytes leading to prolongation of action potential duration and/or QT interval which is associated with malignant arrhythmias [20]. In patients with rheumatoid arthritis, elevated inflammatory markers like IL-6 and CRP are known to be associated with QTc prolongation. Interestingly both cases in our cohort presented with QTc prolongation >500 ms and elevated inflammatory markers as shown in table 2. [21] This suggests that therapeutic interventions targeting inflammatory cytokines can help in ameliorating the effects of systemic inflammation to reduce acute cardiovascular complications including VT/VF storms while promoting recovery from multi-organ dysfunction.
Hemodynamic instability and hyperadrenergic state
Severe SARS CoV-2 infection can cause sepsis with hemodynamic instability and shock. This can lead to organ level cardiac ischemia resulting in scarring or fibrosis. Functional electrical pathways can form in the scar tissue, creating re-entrant circuits that cause ventricular arrhythmias [22]. Although scars are commonly caused by ischemic events, replacement fibrosis can also occur in nonischemic cardiomyopathies. Unfortunately, antiarrhythmic drugs tend to have poor efficacy in VAs due to scars [22].
Alternatively, as a response to cardiac injury, there may be a compensatory response with neurohumoral system activation, leading to sympathetic hyperactivity (hyperadrenergic state) and reduced vagal tone, which helps maintain cardiac output. However, if the cardiac sympathovagal imbalance continues, it creates a maladaptive environment of continued sympathetic activity resulting in cardiac tissue remodeling and ultimately paving pathways for fatal malignant arrhythmias, including electrical storm [23].
Hypoxia and acidosis
Multiple studies have reported acute respiratory distress syndrome and pulmonary embolism as common complications of severe COVID-19 [24]. Resultant hypoxia can predispose patients to tachycardia which further increases oxygen demand of the cardiomyocytes. Decreased oxygen in the cardiomyocytes alters the function of multiple ion channels, including the L-type Ca2+ ion channel, voltage-gated sodium channels, and outward potassium currents, inducing increased oxidative stress through the generation of reactive oxygen species [25]. Additionally, acidosis secondary to hypercapnia in respiratory failure settings can cause persistent membrane depolarization and reduced phase 0 slope of the cardiac action potential in the ventricular fibers [26]. These changes act as triggers for prolonged action potential, early afterdepolarization, and delayed afterdepolarization [27]. These electrophysiological abnormalities together promote ventricular arrhythmias via both non-re-entrant and re-entrant mechanisms [27]. Figure 4 summarizes the mechanisms via which hypoxia and hypercapnia can lead to ventricular arrhythmias [25].
Proarrhythmic drugs
It is crucial to be aware of the proarrhythmic effects of some of the drugs commonly used in the treatment of COVID-19. In the context of systemic inflammation, hemodynamic and/or metabolic instability, proarrhythmic drugs used in the treatment of COVID-19 should be targeted to reduce the burden of arrythmias. Case 1 received a onetime dose of bamlanivimab and case 2 was treated with a 5-day course of dexamethasone and remdesivir in combination. Other than systemic steroids no other anti-inflammatory drugs were used in the two reported cases.
One group of drugs that has been extensively researched during the COVID-19 pandemic is chloroquine and hydroxychloroquine (HCQ). They are mainly used for their anti-malarial properties, however, these drugs received emergency use authorization during the early days of the pandemic based on limited-quality and non-randomized data. Multiple studies have now concluded that chloroquine or HCQ does not improve outcomes in SARS CoV-2 infected individuals or act as a prophylaxis to prevent symptomatic infection [28]. Notably, the RECOVERY trial confirmed this analysis by reporting no significant improvement in 28-day mortality with the use of chloroquine or HCQ [29]. Additionally, the chronic use of chloroquine or HCQ is associated with QTc prolongation by binding to and inhibiting the hERG-potassium channel, thereby blocking the delayed rectifier potassium current leading to prolonged ventricular repolarization. Delayed ventricular repolarization enables early afterdepolarizations, which can trigger torsades de pointes and other ventricular arrhythmias [30].
Use of chloroquine or HCQ was initially combined with azithromycin which is used to treat gram-positive and atypical bacterial respiratory infections. Additionally, azithromycin has an anti-inflammatory effect via the downregulation of inflammatory cytokines. Numerous studies at the start of the pandemic reported that patients treated with azithromycin in addition to HCQ had a reduction in detectable viral load, which led to widespread use of the HCQ-azithromycin combination in COVID-19 patients [31]. However, randomized trials have now demonstrated more adverse events, including QTc prolongation in patients who received the HCQ-azithromycin combination [32]. In addition to QTc prolongation, sustained and non-sustained monomorphic ventricular tachycardias have also been reported with the combination of these drugs [33]. Therefore, the CDC recommends against the use of HCQ and azithromycin in hospitalized or non-hospitalized patients as the cardiac risk imposed by the concurrent use of these medications increases the risk of serious cardiac arrhythmias.
Based on anecdotal evidence, protease inhibitors like lopinavir and ritonavir (Kaletra) have also been considered for the treatment of SARS CoV-2 infection. However, results of 2 large control trials, RECOVERY and SOLIDARITY, have reported failure to reduce mortality, need for mechanical ventilation, or duration of hospitalization [29, 34]. A study on the triple combination therapy of Azithromycin, lopinavir/ritonavir and chloroquine or HCQ resulted in extreme QTC prolongation in 23% of hospitalized COVID-19 patients, with a TdP incidence in 1.14% of study population [35]. Studies have documented association of remdesivir with sinus bradycardia but no such association has been reported with hemodynamic instability or ventricular arrythmias [36].
Risk and Consequences of COVID-19-associated Ventricular Tachycardia/Ventricular Fibrillation Storm
Cardiac viral infection with a high inflammatory burden predisposes patients to arrhythmias, especially if other metabolic dysfunctions are present. According to the American College of Cardiology, the overall incidence of arrhythmias due to COVID-19 is 16.7%. The incidence is lower in mild infection (8.9%) and increases to 44.4% in severe illnesses [6]. Supraventricular tachycardia is the most common type of arrhythmia noted in COVID-19 patients [37]. A study reported that sinus tachycardia resulting from hypoxia, hypovolemia, and fever was the most common supraventricular tachycardia, followed by atrial fibrillation [37]. Other supraventricular tachycardias such as atrioventricular nodal reentry tachycardia and conduction blocks continue to be reported but are not well documented due to the benign nature of these arrhythmias [38].
Numerous studies have documented increased proportions of patients developing ventricular arrhythmias in COVID-19. A study by Guo et al. reported VT/VF in 5.9% of COVID-19 patients, with the majority of the cases in patients with myocardial injury [4]. In a large retrospective survey of 827 patients from 12 countries, 21% of the patients admitted for COVID-19 developed ventricular arrhythmias defined as VT, non-sustained VT, or VF. Patients with VT had equal proportions of monomorphic and polymorphic VT (4% each) and 3.4% had VF [39]. Ventricular arrhythmias were associated with significant mortality when compared to atrial arrhythmias and only 38% of these patients survived to hospital discharge. Other than isolated case reports, observational studies documenting the prevalence of VT/VF storm observed in COVID-19 patients are still lacking [18, 19, 40]. Collectively, these studies suggest that malignant ventricular arrhythmias including VT/VF storm in the context of COVID-19 are more commonly observed in patients with comorbidities and those requiring intensive care unit admission.
Treatment, Prevention, and Monitoring
COVID-19-related VAs in acute settings should be treated with intravenous amiodarone (American College of Cardiology/American Heart Association – Class of Recommendation 1 and Level of Evidence A). For cases of new malignant VAs unrelated to QT prolongation, imaging via transthoracic echocardiography is warranted to assess ventricular function. Cardiac magnetic resonance imaging should also be considered for myocardial involvement. According to European Society of Cardiology guidelines, intravenous lidocaine is a less effective alternative to amiodarone but may be used, especially if underlying ischemia is suspected (Figure 5) [41]. Temporary pacemaker implantation for overdrive termination or anti-tachycardia pacing is an option for emergency cases. Following recovery from acute SARS CoV-2 infection, the need for prevention with either catheter ablation or ICD implantation for secondary prophylaxis should be considered [41]. Additionally, a personalized approach for ICD programming is required to balance unnecessary ICD shocks vs. detecting potential life-threatening VAs.
The general consensus among experts is that patients who developed overt cardiac disease should be closely monitored and reassessed during the acute phase of the SARS CoV-2 infection. Risk stratifying patients is important during recovery. Some have proposed that patients at high risk should receive repeat transthoracic echocardiography and an electrocardiogram 2–6 months after COVID-19 diagnosis [42]. Additional testing, including Holter monitoring, stress testing, and cardiac magnetic resonance imaging, can be considered in some cases to guide return to normal activity or aerobic exercise, including competitive sports.
Study Limitations
This study has several limitations. First, given the observational nature of the study, the association between ICD shocks for COVID-19 induced VT/VF storm cannot be interpreted as causal. Second, in patients with a history of arrhythmias, numerous factors other than COVID-19 may play a role in ICD shocks. Finally, this cohort of ICD patients is a unique patient population with large numbers of comorbidities that may not be representative of the general population and hence reduces generalizability of these findings.