Address for Correspondence:
Joseph G. Akar, MD, PhD
Section of Cardiovascular Medicine / Yale University School of Medicine
Dana 3, 789 Howard Ave
New Haven, CT 06520
Tel: 203-737-4716
Fax 203-785-6506
Email:
joseph.akar@yale.edu
We thank Medina et al. for their interest in our recent work on QTc
prolongation associated with treatment of COVID-19 patients with
hydroxychloroquine and azithromycin. As they appropriately point out in
their letter, genetic variation is likely a significant determinant of
QT prolongation in the population at large and in COVID-19 patients
specifically. While drugs causing acquired long QT syndrome and torsades
de pointes are generally blockers of IKr, repolarization
results from the aggregate of multiple inward and outward currents.
Patients with sub-clinical defects in any of these ion channels can have
normal or only slightly prolonged baseline QT intervals, but may possess
decreased repolarization reserve leading to an exaggerated response to
IKr blockade (1). In our study, a baseline QTc of
> 460 ms was associated with excessive QTc prolongation,
and this likely represents a group of patients with sub-clinical cardiac
ion channel mutations (so called “first hit”) (2). We also agree that
many patients with latent mutations demonstrate a normal baseline QT,
which gets prolonged with the addition of a drug or a change in the
clinical condition “second hit” (3). The patients in our study who
exhibited QTc prolongation were generally acutely ill, and displayed
“multiple hits” that led to QTc prolongation and it is certainly
plausible that many may have had sub-clinical cardiac ion mutations. We
therefore wholeheartedly agree that pharmacogenetics should be
considered in studies of drug-induced QT prolongation, however this
information is rarely available to include for acutely ill patients. And
while it makes sense to obtain genetic profiles prior to administration
of QT-prolonging medications, that can only be performed in the elective
outpatient setting, while taking into consideration medical, ethical and
social issues related to asymptomatic genetic screening (e.g. cost,
reimbursement, informed consent, etc…). There is significant
interest in building genomic databases, and when this becomes a reality
for the population at large we believe that genetic information should
certainly be included in studies of QT prolongation.
- Roden DM Long QT syndrome: reduced repolarization reserve and the
genetic link. J Intern Med. 2006 Jan; 259(1):59-69.
- Napolitano C, Schwartz PJ, Brown AM, et al. Evidence for a cardiac ion
channel mutation underlying drug-induced QT prolongation and
life-threatening arrhythmias. J Cardiovasc
Electrophysiol. 2000;11:691–6
- Sauer AJ and Newton-Cheh C. Clinical and genetic determinants of
torsade de pointes risk. Circulation. 2012;125:1684-94.