key: cord-0688787-kn1lcsia
authors: Wu, Cheng-I.; Postema, Pieter G.; Arbelo, Elena; Behr, Elijah R.; Bezzina, Connie R.; Napolitano, Carlo; Robyns, Tomas; Probst, Vincent; Schulze-Bahr, Eric; Remme, Carol Ann; Wilde, Arthur A.M.
title: SARS-CoV-2, COVID-19 and inherited arrhythmia syndromes
date: 2020-03-31
journal: Heart Rhythm
DOI: 10.1016/j.hrthm.2020.03.024
sha: eb54cc309adbd640bff2254582bc095b5e0ff2fc
doc_id: 688787
cord_uid: kn1lcsia

Abstract Ever since the first case was reported at the end of 2019, the SARS-COV-2 virus and associated lung disease COVID-19 has spread throughout the world and has become a pandemic. In particular, the high transmission rate of the virus has made it a threat to public health globally. Currently, there is no proven effective therapy against the virus, and the impact on other diseases is also uncertain, especially inherited arrhythmia syndrome. Arrhythmogenic effect of COVID-19 can be expected, potentially contributing to disease outcome. This may be of importance for patients with an increased risk for cardiac arrhythmias, either secondary to acquired conditions or co-morbidities or consequent to inherited syndromes. Management of patients with inherited arrhythmia syndromes such as Long QT syndrome, Brugada syndrome, Short QT syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia in the setting of the COVID-19 pandemic may prove particularly challenging. Depending on the inherited defect involved, these patients may be susceptible to pro-arrhythmic effects of COVID-19-related issues such as fever, stress, electrolyte disturbances and use of antiviral drugs. We here describe the potential COVID-19 associated risks and therapeutic considerations for patients with distinct inherited arrhythmia syndromes and provide recommendations, pending local possibilities, for their monitoring and management during this pandemic.

A registry of 1099 cases with COVID-19 reported a higher prevalence of hypertension 76 (23.7% vs. 13.4%) and coronary artery disease (5.8% vs. 1.8%) in severely affected versus 77 non-severely affected patients. 4 Another study, of 138 hospitalized COVID-19 78 patients compared patients admitted to the intensive care unit (ICU) and non-ICU patients. 79

Higher rates of hypertension (58.3% vs. 21.6%, p <0.001) and cardiovascular disease (25.0% 80 vs. 10.8%, p=0.04) were observed in ICU patients. 1 This indicates that patients with 81 pre-existing cardiovascular disease may have a worse prognosis than others although age could 82 be one of the confounders. Furthermore, it is also essential to understand that although most 83 clinical presentations relate to the respiratory system, the disease may also impact on the 84 cardiovascular system. 5 Besides the respiratory system, ACE2 is expressed in the human 85 cardiovascular system including the heart 6 and a number of mechanisms have been put 86 forward whereby SARS-CoV-2 may cause myocardial injury. These include mechanisms 87 involving derangement of ACE2 signal pathways (animal studies have shown that cellular 88 ACE2 levels decrease upon SARS-CoV infection), 6 cytokine storm and myocarditis. 7,8 89

Occurrence of myocardial involvement and severity thereof varies among affected 90 individuals. While myocardial damage evidenced by high cardiac markers such as hs-TnI has 91 been recognized 9 and fulminant myocarditis has been reported, 8 whether cardiovascular 92 complications include malignant arrhythmias is not yet known. In the afore-mentioned study 93 of 138 hospitalized COVID-19 patients, arrhythmia (not further specified) was reported in 17% 6 of total patients and in 16 of 36 patients admitted to the ICU. 1 Therefore, an arrhythmogenic 95 effect of COVID-19 could be expected, potentially contributing to disease outcome. This may 96 be of importance for patients with an increased risk for cardiac arrhythmias, either secondary to 97 acquired conditions, co-morbidities, or consequent to inherited syndromes. Management of 98 patients with inherited arrhythmia syndromes such as Long QT syndrome, Brugada syndrome, 99

Short QT syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia in the 100 setting of the COVID-19 pandemic may prove particularly challenging. Depending on the 101 inherited defect involved, these patients may be susceptible to pro-arrhythmic effects of 102 COVID-19-related issues such as fever, stress, electrolyte disturbances and use of antiviral 103 drugs. Hence, additional precautions and preventive measures are recommended, including 104 ECG monitoring, aggressive antipyretic treatment, and more stringent social distancing to 105 prevent infection. 10 We here describe the potential COVID-19 associated risks and therapeutic 106 considerations for patients with distinct inherited arrhythmia syndromes and provide 107 recommendations for their monitoring and management during this pandemic. 108

The Long QT syndrome (LQTS) is characterised by abnormally prolonged ventricular 110 repolarization and an increased risk of the malignant arrhythmia Torsades de Pointes and 111 ventricular fibrillation that may lead to sudden death. LQTS is an inheritable condition caused 112 by pathogenic variants in genes encoding ion channels (primarily KCNQ1, KCNH2, SCN5A). 7 An often-faced clinical situation, however, is acquired QT-interval prolongation, that occurs 114 for instance during myocardial ischemia, hypothermia, as a result of treatment with a wide 115 range of drugs, hypokalaemia or sepsis. Severe QTc-prolongation due to these conditions 116 might similarly result in malignant arrhythmias. Rather commonly, patients who have severe 117 forms of acquired QT-prolongation also have a genetic predisposition for 118 QTc-prolongation, 11,12 but without such extreme provocation these patients generally have 119 normal QT-intervals. In fact, many LQTS patients may also have QT-intervals within normal 120 limits in resting conditions, 13 although this still puts them at higher risk for malignant 121 arrhythmias, 14 especially during provocations such as the use of QTc-prolonging drugs. 15 122

Whereas severe forms of inherited LQTS often surface during (early) childhood (from infants 123 to adolescents), 14,16 acquired QT-prolongation generally occurs in older patients because these 124 critical provocative events more often occur in older patients. 125

There are several issues that require attention when discussing COVID-19 in relation to 127 inheritable or acquired QT-prolongation. 128

The most important determinant of risk for malignant arrhythmias in patients with LQTS 129 or in acquired QT-prolongation, is the use of one or more QTc prolonging drugs in the setting 130 of severe manifestations of COVID-19. Many drugs (either with cardiac or non-cardiac 131 indications) have the ability to block cardiac potassium currents, impairing ventricular 132 8 repolarisation with subsequent prolongation of the QT-interval and an increased risk for 133 malignant arrhythmias. 15 In addition, many drugs may alter drug metabolism, e.g. due to 134 inhibition of CYP3A4, which may further increase plasma levels of QT-prolonging drugs and 135 further increase risk. Of special interest in COVID-19 is that there are indications that 136 chloroquine and hydroxychloroquine might be of value. 17 137

Chloroquine is one of the most widely used anti-malarial drugs world-wide, but it has also 138 been investigated as a potential broad-spectrum anti-viral drug. 18 Amongst its mechanisms, 139 chloroquine appears to interfere with the terminal glycosylation of ACE2 and may thus 140 negatively influence virus-receptor binding and abrogate infection. 19-21 However, chloroquine 141 is closely related to quinidine, and while the latter is used as an anti-arrhythmic drug in 142

Brugada syndrome and idiopathic forms of ventricular fibrillation, it is also well known for its 143 QT-prolonging effects and has been associated with QT related malignant arrhythmias. 144

Luckily, the QT-prolonging effect of chloroquine is very modest, and in general it does not 145 result in clinically significant QT-prolongation in patients without LQTS. 22 146

Hydroxychloroquine sulfate, a less toxic derivative of chloroquine, is widely used in the 147 chronic treatment of autoimmune diseases without significant effects on ECG parameters, 23 148 and was recently shown to also efficiently inhibit SARS-CoV-2 infection in vitro. 24 However, 149 both chloroquine and hydroxychloroquine are metabolised by CYP3A4, and COVID-19 150 treatment with (hydroxy)chloroquine can be combined with additional anti-viral treatments 9 such as ritonavir plus lopinavir (both potent CYP3A4 inhibiting drugs; their combination is 152 associated with QT-prolongation), azithromycin (besides a macrolide antibiotic also 153 investigated for its antiviral properties, with also (weak) CYP3A4 inhibition and associated 154 with QT-prolongation) 25,26 , or remdesivir (an investigational drug for which metabolism and 155 possible QT prolonging effects are not yet resolved). Combining (hydroxy)chloroquine with 156 these drugs might thus result in higher plasma levels and significant QT-prolongation. Hence, 157

we advise monitoring QT-intervals and cardiac rhythm if starting these drugs given the 158 increased risk for malignant arrhythmias ( Figure 1 ). In addition, physicians should be aware of 159 the alpha-blocking effects of (hydroxy)chloroquine, which might result in hypotension. 160

Another issue is fever. The effect of fever is, in contrast to patients with for example BrS 161 (see below), much less evident in patients with LQTS. A possible exception are patients, with 162 specific LQTS 2 mutations, presenting with fever-triggered arrhythmias which are based on 163 temperature sensitive mutant channels (i.e. less current with higher temperature). 27 As most 164 patients hospitalised for COVID-19 have fever, 4 patients with known LQTS will thus generally 165 not be at increased risk. The separate contribution of fever in acquired QT-prolongation is not 166 well known, but sepsis is a denominator of risk of acquired QT-prolongation 28 , and septic 167 shock is one of the clinical scenarios in COVID-19. 4 168 Finally, interpretation of the QT-interval is not easy, 29 but guidance is available. 13 The importance of fever in BrS patients is now well-established. [33] [34] [35] In 24 patients with 211

BrS, 3 of whom had a fever-triggered cardiac arrest, the increase in body temperature reduced 212 the PR interval in control individuals, but increased PR interval, QRS width, and the maximum 213 J-point in BrS patients. 34 Another study showed that fever-associated BrS seems to be 214 associated with a higher future risk of LTE's compared to drug-induced type 1 pattern. 35 215

Finally, fever seems to be particularly relevant in children. 33 Indeed, in a registry with 216 symptomatic BrS patients (the SABRUS registry) approximately 6% of LTE's were associated 217 with fever and the highest rate of fever-triggered LTE's was observed in the very young (65%, 218 age ≤5 years). In the age range 16 to 70 years, only 4% of the LTE's was related to fever. In the 219 elderly (>70 years) this percentage increased to 25%. 33 220

In the setting of fever, the presence of a pathogenic variant in SCN5A may be particularly 221 relevant. In a single center series of 111 patients with BrS, 22 presented with a cardiac arrest, 4 222 of which were fever related. Three of these 4 patients harbored a pathogenic variant in 223 SCN5A. 34 In the SABRUS registry, the percentage of SCN5A pathogenic variants was 77% in 224 children and 27% in adults with a LTE. 33 The authors also performed an analysis of all 225 published cases (up to 2018) with fever-triggered LTE's (40 patients in 22 reports) revealed the 226 presence of a putatively pathogenic variant in SCN5A was found in 13 (68%) of 19 patients 227 tested. 33 Moreover, in a multicenter pediatric population of 106 patients, 10 patients had a LTE 228 during follow-up, which was triggered by fever in 27%; all of the latter patients were positive 229 for a pathogenic SCN5A variant. Finally, preliminary data in a pediatric cohort indicated that 230 mainly children with a SCN5A mutation developed a type 1 ECG during fever (43.8% of 231 children who developed a type 1 ECG during fever had a SCN5A mutation vs 4.2% of children 232 without a type 1 during fever) and had events during follow-up (7/21 vs 0/47). 36 These studies 233 collectively indicate that sodium channel function is sensitive to temperature. This sensitivity 234 may be due to altered temperature-sensitive kinetics, in particular accelerated inactivation, 37 235 and/or decreased sodium channel expression at higher temperatures. 38 3. If these higher risk patients develop a high fever (>38.5C) despite paracetamol 247 treatment, they will need to attend the emergency department*. The emergency 248 department must be forewarned to allow assessment by staff with suitable protective 249 equipment. Assessment should include an ECG** and monitoring for arrhythmia. If an 250 ECG shows the type 1 Brugada ECG pattern, then the patient will need to be observed 251 until fever and/or the ECG pattern resolves. If all ECGs show no sign of the type 1 ECG 252 pattern, then they can go home to self-isolate. Hence, based on current knowledge, SQTS patients do not seem to be at particular risk when 275 they are affected by Potential drugs for COVID-19 patients, like chloroquine, might actually be beneficial for 277 SQTS patients due to lengthening of their QT-interval, as has been suggested by modelling 278 data for SQTS type 1 (KCNH2-related 44 ) and type 3 (KCNJ2 related 44,45 ). There are no clinical 279 data as far as we are aware. 280

We therefore do not believe that there is a particular concern when SQTS patients are 281 infected with SARS-CoV-2. As mentioned above, exercise and emotional circumstances constitute specific triggers for 291

LTE. An increased heart rate alone (pacing-induced), as an important symptom of fever, does 292 not appear to be sufficient for the induction of ventricular arrhythmias. 48 Fever, as a specific 293 trigger has not been described. Whether or not the stressful circumstances that COVID-19 294 patients find themselves in will lead to an increased burden of arrhythmias can only be 295 speculated upon. 296

The antiviral therapy proposed for COVID-19 is not expected to lead to increased risk. 297

The only potential deleterious pharmacological interaction in these patients are drugs with 298 alpha or beta adrenoceptor mimetic activity, which may be used in cases in need of 299 hemodynamic support. Intravenous epinephrine has been used to unmask ventricular 300 arrhythmias and initial data suggested that epinephrine was more effective than exercise testing 301 in unmasking ventricular arrhythmias. 49 Later studies revealed, however, a low sensitivity and 302 high specificity (with the exercise test as the gold standard 50 ). Nevertheless, based on their 303 pathophysiological mechanism of action, epinephrine, isoproterenol and dobutamine, all alpha 304 and/or B1 receptor agonists, should probably be avoided. Milrinone, the most widely used 305 phosphodiesterase 3 inhibitor, acts by decreasing the degradation of cyclic adenosine 306 monophosphate (cAMP). This may potentially stimulate the RyR2 receptor and must thus be 307 used with caution. However, with continuation of the beta blockers (as we recommend, see 308 below) this may not be that relevant because betablockers suppress milrinone-induced 309 increased Ca-leak. 51 CPVT patients, in particular those who were symptomatic prior to 310 diagnosis, should stay on their beta blocker treatment with or without flecainide as long as is 311 tolerated hemodynamically. Flecainide does have interactions with Ritonavir/Lopinavir and 312

chloroquine, yet we believe that it is an important enough therapy not to stop in these 313 particularly stressful circumstances. 314

Based on the above we also suggest avoidance of epinephrine in the setting of a VT/VF 315 arrest if possible. This is probably the only resuscitation setting where epinephrine is 316 contraindicated. 52 317

Patients with inherited arrhythmia syndromes may be at an increased pro-arrhythmic risk 319 

Clinical Characteristics of 138 Hospitalized Patients With 325 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

A familial cluster of pneumonia associated with the 2019 327 novel coronavirus indicating person-to-person transmission: a study of a family cluster

A pneumonia outbreak associated with a new 330 coronavirus of probable bat origin

Determination and interpretation of the QT 352 interval

Safe drug 357 use in long QT syndrome and Brugada syndrome: comparison of website statistics

Long-QT Syndrome After Age 40

Remdesivir and chloroquine effectively inhibit the 362 recently emerged novel coronavirus (2019-nCoV) in vitro

New insights into the antiviral 364 effects of chloroquine

COVID-19: a recommendation to examine the effect of 366 hydroxychloroquine in preventing infection and progression

Hydroxychloroquine and Azithromycin as a 369 treatment of COVID-19: preliminary results of an open-label non-randomized clinical trial

Heart conduction disorders related to 375 antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with 376 hydroxychloroquine for connective tissue diseases

Hydroxychloroquine, a less toxic derivative of chloroquine, is 378 effective in inhibiting SARS-CoV-2 infection in vitro

QT Prolongation in Real-World Practice

Azithromycin Causes a Novel Proarrhythmic

Fever-induced QTc prolongation and ventricular 384 arrhythmias in individuals with type 2 congenital long QT syndrome

Development and validation of a risk score to 387 predict QT interval prolongation in hospitalized patients

Inaccurate electrocardiographic interpretation of 390 long QT: the majority of physicians cannot recognize a long QT when they see one

Extracellular potassium modulation of drug block of IKr

Implications for torsade de pointes and reverse use-dependence

J-Wave syndromes expert consensus 395 conference report: Emerging concepts and gaps in knowledge

Drugs and Brugada syndrome patients: review of 398 the literature, recommendations, and an up-to-date website (www.brugadadrugs.org)

Fever-related arrhythmic events in 401 the multicenter Survey on Arrhythmic Events in Brugada Syndrome

Fever Increases the Risk for

Cardiac Arrest in the Brugada Syndrome

A low-dose β1-blocker in combination with 449 milrinone improves intracellular Ca2+ handling in failing cardiomyocytes by inhibition of 450 milrinone-induced diastolic Ca2+ leakage from the sarcoplasmic reticulum

The Cardiac Arrest Where Epinephrine Is Contraindicated