Genetic Variant Might Contribute to Racial Disparity in COVID-19 Cardiac Mortality

By Will Boggs, MD

May 18, 2020

NEW YORK (Reuters Health) — A genetic variant that increases the risk of drug-induced long QT syndrome (LQTS) and sudden cardiac death (SCD) could contribute to the higher COVID-19-related mortality seen in African Americans, researchers report.

In one study, for example, African Americans accounted for 26% of confirmed COVID-19 cases but 43% of COVID-19 deaths. In another study, COVID-19 mortality in predominantly black counties was 6-fold higher than in predominately white counties in the United States. It's not clear what accounts for these differences.

Dr. Michael J. Ackerman from Mayo Clinic, Rochester, Minnesota and colleagues propose that a genetic variant seen almost exclusively in individuals of African descent (p.Ser1103Tyr-SCN5A), which confers an increased risk for drug-induced LQTS and SCD, could increase the risk for ventricular arrhythmia and SCD among African American patients with COVID-19.

About 8% of African Americans have this genetic variant.

Under normal circumstances, this variant is unlikely to manifest clinically. However, in the setting of hypoxia, seen in many COVID-19 cases, pathologic late sodium currents associated with this variant can prolong ventricular action potential duration and predispose to ventricular arrhythmias/SCD, according to the online report in Heart Rhythm.

The elevation of IL-6 triggered by SARS-CoV-2 infection can also contribute to action potential duration prolongation, cardiac sympathetic nervous system hyperactivity, and inhibition of enzymes involved in the metabolism of some QT-interval-prolonging drugs.

Taken together, these observations suggest that 1 in 13 African Americans might be at substantially increased risk for potentially lethal ventricular arrhythmias during the COVID-19 pandemic. How this speculation might be tested remains unclear.

In the meantime, the authors recommend avoiding the use of QT-interval-prolonging drugs (for example, hydroxychloroquine, azithromycin, and lopinavir/ritonavir); exploring the association between this genetic variant and rates of sudden death and COVID-19-related mortality in areas with medical record-linked DNA biobanks; investigating the feasibility of point-of-care genetic testing for this variant; and evaluating the clinical utility of QT-interval-shortening agents and anti-IL-6-targeted therapies to better protect at-risk individuals.

Dr. Clyde W. Yancy, from Northwestern University, Feinberg School of Medicine, Chicago, who is deputy editor of JAMA Cardiology, told Reuters Health by email, "As the crisis struck North America, among the many emerging observations has been the disproportionate burden of morbidity and mortality due to COVID-19 seen in the Black community. The increased risk of infection with the novel coronavirus and the markedly increased risk of death due to COVID-19 disease are not only consistent with striking health disparities but may represent the most egregious disparities yet seen. Clearly, COVID-19 has dramatically exposed the weak spots in our social fabric and illuminated our most vulnerable populations."

"We have long known that one channel in particular, SCN5A, does vary in function according to inherited genetics and those variations in function do create a theoretical risk profile that leads to certain electrical abnormalities (as may occur with the use of hydroxychloroquine) that might lead to heart rhythm disturbances, even sudden death," he said. "This scenario may be further exacerbated under the circumstances of a severe acute illness with changes in oxygen levels and body chemistries (acidosis)."

"Thus, on a theoretical basis, a risk may be inferred that tracks to an inherited variation in an important electrical channel in the heart and this risk may impact Blacks disproportionately and lead to sudden death," Dr. Yancy said. "Yet, the elegant science involved here is a hypothesis that is not yet proven."

"Much more research is needed to know: 1) is sudden death a major cause of mortality in COVID19? 2) are Blacks at unique risk for sudden death in COVID19? and 3) should practice change if data emerge to verify this risk and the imputed cause?" he said. "In the absence of a proven hypothesis with compelling data, we accept the theoretical discussion but suggest that current algorithms of care remain unchanged."

Dr. Ackerman did not respond to a request for comment.

SOURCE: Heart Rhythm, online May 4, 2020.