key: cord-0868725-jni56jzf
authors: Giudicessi, John R.; Roden, Dan M.; Wilde, Arthur A.M.; Ackerman, Michael J.
title: Genetic Susceptibility for COVID-19-Associated Sudden Cardiac Death in African Americans
date: 2020-05-05
journal: Heart Rhythm
DOI: 10.1016/j.hrthm.2020.04.045
sha: 8a9fd0107921eb2ea7eb600dee9f6068288753ca
doc_id: 868725
cord_uid: jni56jzf

nan

Since emerging from Wuhan, China in late 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID- 19) , has infected over 3.2 million individuals worldwide and nearly 1 million in the United States (as of 04/29/2020). 1, 2 Despite the institution of measures designed to "flatten the curve", COVID-19 has claimed the lives of > 225,000 individuals worldwide and > 60,000 individuals in the United States alone (as of 04/29/2020). 2 Of note, mortality estimates in some of the hardest hit regions have already or may need to be revised to account for a spike in sudden deaths occurring at home. 3, 4 Although most of these deaths are likely directly attributable to COVID-19 (e.g. pulseless electrical activity/respiratory arrests), many of the same regions within the United States have also seen the outpatient prescription volume of COVID-19-direct, heart-corrected QT interval prolonging drug(s), specifically hydroxychloroquine, rise by as much as 22,700% compared to the same time period (03/15-31) in 2019. 5 Importantly, recent studies have shown that between 11% and 25% of hospitalized COVID-19 patients treated with chloroquine or hydroxychloroquine and azithromycin had QTc values rise above the critical 500 ms threshold. 6, 7 As a result, a substantial number of COVID-19 patients, prescribed these so-called "corona cocktails", may be at increased risk of developing drug-induced long QT syndrome (DI-LQTS) which could deteriorate into drug-induced torsades de pointes (DI-TdP), or worse, druginduced sudden cardiac death (DI-SCD). 8, 9 Therefore, it stands to reason that the same phenomenon (DI-LQTS/DI-TdP) that has already halted one chloroquine/hydroxychloroquine clinical trial 7 and led the Food and Drug Administration to caution against the use of chloroquine/hydroxychloroquine outside of the hospital setting/clinical trial 10 could also be contributing, at least in small part, to the increase in sudden deaths observed in some COVID-19

epicenters.

In addition, the COVID-19 pandemic has highlighted already alarming health disparities in the United States. For example, in Illinois where age, gender, and racial demographic data are reported for all COVID-19 cases, African Americans account for 26% of confirmed COVID-19

cases, but 43% of COVID-19 deaths. 11 A similar trend has been observed across the United States where COVID-19 mortality rates in predominantly black counties are 6-fold higher than in predominantly white counties. 12 Although this phenomenon is likely explained by the convergence of multiple cultural and socioeconomic factors 12 , an underlying genetic susceptibility to SARS-CoV-2 infection, its sequelae (such as hypoxia and inflammation), or the potentially lethal side effects of COVID-19-directed therapies (i.e. DI-TdP and DI-SCD), assuming equal exposure to these medications, could also contribute.

Current evidence supports the notion that the common ion channel variants p.Asp85Asn-KCNE1 and p.Ser1103Tyr-SCN5A confer an increased risk for DI-LQTS and DI-SCD ( Table   1) . 13 Importantly, p.Ser1103Tyr-SCN5A is seen almost exclusively in individuals of Africandescent and its frequency in that population (~8%) is higher than that of p.Asp85Asn-KCNE1 (0.2-2.5% depending on ancestry; 0.2% in individuals of African origin; Table 1 ). 13 Furthermore, unlike p.Asp85Asn-KCNE1 whose pro-arrhythmic potential is largely limited to DI-LQTS risk, the modest increase in late/persistent sodium current generated by p.Ser1103Tyr-SCN5A is accentuated markedly by hypoxia/acidosis and has been linked to an increased risk of ventricular arrhythmia (VA) and SCD in African Americans across the age spectrum. [13] [14] [15] [16] Given the potential of p.Ser1103Tyr-SCN5A to exacerbate outcome-related health disparities in the COVID-19 pandemic, this review was assembled to raise awareness of the multiple mechanism(s) whereby the pro-arrhythmic p.Ser1103Tyr-SCN5A common variant may increase risk for VA/SCD amongst those of African descent as well as the importance of identifying modifiable risk factors for mortality during the COVID-19 pandemic.

In individuals of African descent, the common SCN5A-encoded Nav1.5 sodium channel variant p.Ser1103Tyr-SCN5A has been associated with an increased risk of VA/SCD. 14, 15, 17 Of note, this pro-arrhythmic potential has been reported to be enhanced by non-genetic risk factors known to reduce cardiac repolarization reserve [e.g. hypokalemia and QTc-prolonging medication exposure; odds ratio 8.7 (95% confidence interval 3.2 -23.9, P=0.00003)] 17 and/or structural heart disease [relative risk 8.4 (95% confidence interval 2.1 to 28.6, P=0.001)] ( Table 1) . 14, 15 Furthermore, p.Ser1103Tyr-SCN5A was associated with potentiation of the QT-prolonging effect of hypokalemia in the 4,476 participants of the Jackson Heart Study suggesting that p.Ser1103Tyr-SCN5A contributes to decreased cardiac repolarization reserve at a populationspecific level. 18 In addition, two population-based studies reported that p.Ser1103Tyr-SCN5A is over-represented in African American sudden infant death syndrome (SIDS) victims 16, 19 providing additional epidemiologic evidence that p.Ser1103Tyr-SCN5A confers an increased risk of sudden death in African Americans regardless of age.

Besides this epidemiologic evidence, in vitro functional characterization by two independent groups demonstrated that p.Ser1103Tyr-SCN5A alters the inactivation gating of the Na v 1.5 sodium channel [negative shift in the voltage dependence of steady state inactivation (V 1/2 )] and accentuates the sustained/late sodium current that is also the signature of the electrophysiological phenotype displayed by the type 3 long QT syndrome (LQT3)-pathogenic variants. 16, 17, 20 That said, the experimental conditions (physiologic pH vs. low intracellular pH) under which p.Ser1103Tyr-SCN5A increased the late sodium current differed in the studies of Splawski et al 17 and Plant et al 16 , respectively. Furthermore, neither study demonstrated an in vitro or in silico ability of p.Ser1103Tyr-SCN5A to prolong action potential duration in the absence of a "second hit" such as blockade of the rapid-component of the delayed rectifier potassium current (I Kr ) or intracellular acidosis. This appears to be consistent with i) the exaggerated QTc response to hypokalemia observed in p.Ser1103Tyr-SCN5A-positive Jackson Heart Study participants 18 and ii) a circumstance-dependent pro-arrhythmic state in infants (respiratory acidosis caused by hypoxia/apnea) 16, 19 and older (DI-LQTS in the setting of ≥ 1 QTc-prolonging drug and advanced structural heart disease) p.Ser1103Tyr-SCN5A-positive African Americans. 14-16

Direct and/or indirect myocardial injury/stress, as assessed by cardiac biomarkers such as troponin I and brain-type natriuretic peptide, has emerged as both a prominent and prognostic feature in COVID-19. [21] [22] [23] Of note, in an adjusted Cox regression model, the mortality risk associated with elevated cardiac biomarkers/acute cardiac injury was more significant than age and high-risk co-morbid conditions such as chronic obstructive/fibrotic pulmonary disease, diabetes, and a pre-existing history of cardiovascular disease. 23, 24 In addition, life-threatening VAs (e.g. ventricular tachycardia/ventricular fibrillation) have been documented in ~6% of hospitalized COVID-19 patients and appear to be driven by underlying myocardial injury. 25 Proposed mechanisms of acute myocardial injury and resulting VA risk in patients with COVID-19 include i) direct SARS-CoV-2 myocardial infection (e.g. myocarditis), ii) myocardial stress induced by hypoxemic respiratory failure, and/or iii) an exaggerated immune response that results in high levels of circulating cytokines [i.e. interleukin-6 (IL-6), tumor necrosis factor-α, etc.] directly injuring cardiomyocytes (Figure 1) . [25] [26] [27] Notably, IL-6 may prolong the ventricular action potential via modulation of cardiac ion channel expression/function. 27 Under normal physiological circumstances, Na v 1.5 cardiac sodium channels conduct tiny amount of persistent/late sodium current that contributes minimally to the maintenance of the action potential plateau (i.e. ≤ 0.5% of peak I Na ). 28 However, in the setting of hypoxia, myocardial ischemia, heart failure, and LQT3-causative SCN5A gain-of-function variants, the relative contribution of late sodium current can increase up to ten-fold to 4%-5% of peak I Na . 16, 20, 28, 29 In turn, this "pathologic" late sodium current can prolong ventricular action potential duration (APD) and predispose to VA/SCD.

As discussed previously, p.Ser1103Tyr-SCN5A Na v 1.5 sodium channels function normally under physiologic conditions (e.g. intracellular pH of 6.9 to 7.1). 16 However, when intracellular pH is decreased in vitro to levels consistent with the respiratory acidosis that occurs secondary to hypoxia/prolonged apnea (e.g. intracellular pH of 6.6 to 6.8), p.Ser1103Tyr-SCN5A Na v 1.5 sodium channels generate a pro-arrhythmic, LQT3-like increase in persistent/late sodium current (~5% of peak I Na ). 16 This mechanism was put forward initially to explain the gene-environment interaction(s) responsible for the association between p.Ser1103Tyr-SCN5A and SIDS 16 . However, the profound hypoxia observed in many COVID-19 cases raises reasonable concern that p.Ser1103Tyr-SCN5A could produce a similar, African Americanspecific susceptibility to hypoxia-induced VA/SCD in the setting of SARS-CoV-2 infection/COVID-19 (Figure 1) .

Unfortunately, the increased risk of VA/SCD linked to the potentially pro-arrhythmic p.Ser1103Tyr-SCN5A common variant is likely not limited to the possibility of hypoxia-induced VA/SCD. As succinctly outlined in recent work by Lazzerini et al 27 , the exaggerated immune response triggered by SARS-CoV-2 infection, specifically elevation of IL-6, likely increases arrhythmia risk via i) modulation of cardiac ion channel expression/function leading to APD prolongation (e.g. direct IL-6-mediated blockade of hERG/K v 11.1 potassium channels), ii) cardiac sympathetic nervous system hyperactivity, and iii) inhibition of cytochrome P450 enzymes involved in the metabolism of some QTc-prolonging drugs (e.g. IL-6 and CYP3A4; Figure 1 ). The latter effect of IL-6 is particularly important given that a number of COVID-19 pharmacotherapies (e.g. hydroxychloroquine + azithromycin and lopinavir/ritonavir) under investigation and/or in use clinically are known to prolong the QTc and pre-dispose to DI-TdP/DI-SCD ( Table 2) . 8, 30 Taken together, these data suggest that 1 in 13 African Americans may be at substantially increased risk for potentially lethal VAs, most notably DI-TdP, during the COVID-19 pandemic due to the perfect storm of i) intrinsic genetic-susceptibility (i.e. p.Ser1103Tyr-SCN5A), ii) modifiable environmental risk factors (e.g. electrolyte abnormalities and concurrent QTcprolonging drug use), and iii) COVID-19-specific risk factors (e.g. profound hypoxemia and cytokine storm; Figure 1 ). Whether population-specific genetic risk factors such as p.Ser1103Tyr-SCN5A are contributing to the spike in sudden deaths and racial health disparities observed in COVID-19 epicenters remains to be proven and given the lack of banked DNA in these epicenters, this speculation may not even be testable.

Nevertheless, given the potential for COVID-19 to exacerbate known gene-environment interactions pertaining to the potentially pro-arrhythmic p.Ser1103Tyr-SCN5A common variant, it seems reasonable to i) avoid using COVID-19-directed, QTc prolonging drugs (e.g.

hydroxychloroquine + azithromycin and lopinavir/ritonavir) unless careful, and preferably personal protective equipment (PPE)-sparing, cardiac monitoring can be implemented (Figure  2 ) 8, 31 , ii) explore the association between p.Ser1103Tyr-SCN5A and rates of sudden death and COVID-19-related mortality in areas with medical record-linked DNA biobanks (e.g. United Kingdom Biobank and the Jackson Heart Study), iii) investigate further the feasibility of pointof-care p.Ser1103Tyr-SCN5A genetic testing, and iv) determine the clinical utility of QTcshortening agents such as late sodium current blockers (e.g. mexiletine and lidocaine) and anti-IL-6 targeted therapies (e.g. tocilizumab and sarilumab) 27, 32 to better protect at-risk individuals, especially African Americans in the context of the ongoing COVID-19 pandemic.

Food and Drug Administration. FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. 2020; https://www.fda.gov/drugs/drug-safety-andavailability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19outside-hospital-setting-or. Accessed 04/26/2020.

Illinois Department of Health. COVID-19 statistics. 2020.

Yancy CW. COVID-19 and African Americans. JAMA 2020. 

Akhmerov A, Marban E. COVID-19 and the heart. Circulation Research 2020.

Lazzerini PE, Boutjdir M, Capecchi PL. COVID-19, Arrhythmic risk and inflammation: Mind the gap! Circulation 2020.

Makielski JC. Late sodium current: A mechanism for angina, heart failure, and arrhythmia. Trends Cardiovasc Med Feb 2016;26:115-122.

Belardinelli L, Giles WR, Rajamani S, Karagueuzian HS, Shryock JC. Cardiac late Na(+) current: proarrhythmic effects, roles in long QT syndromes, and pathological relationship to CaMKII and oxidative stress. Heart Rhythm Feb 2015;12:440-448.

Roden The estimated 99 th percentile QTc values, derived from otherwise healthy individuals, which places a patient in the "Green Light" category are < 460 ms before puberty, < 470 ms in men, and < 480 ms in women. We estimate that the baseline QTc assessment will place 90% in "Green Light", 9% in "Yellow Light", and 1% in "Red Light" status. * Severe COVID-19 cases defined as a RR ≥ 30 (adults) or 40 (children), oxygen saturation ≤ 93%, PaO 2 /FiO 2 ratio < 300, or lung infiltrates involving >50% of the lung field after 24-48 hours. No randomized control trial data is available to support the clinical efficacy of any of the COVID-19-directed QTc prolonging drugs despite the FDA's Emergent Use Approval of hydroxychloroquine. Abbreviations: COVID-19, coronavirus disease 19; CV, cardiovascular DI-TdP, drug-induced torsades de pointes; DI-SCD, drug-induced sudden cardiac death; ECG, electrocardiogram; QTc, heart rate-corrected QT interval; and SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Adapted from Giudicessi et al 8 with permission. Copyright © Elsevier, 2020. 

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Gene-environment interaction between SCN5A-1103Y and hypokalemia influences QT interval prolongation in African Americans: the Jackson Heart Study

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