Circulation

PERSPECTIVE

The QT Interval
An Emerging Vital Sign for the Precision Medicine Era?

T
he core vital signs including heart rate, respiratory rate, body temperature, John R. Giudicessi, MD,
and blood pressure can be assessed rapidly and provide critical, objective, PhD
and quantitative insights into the state of the body’s essential functions. Al- Peter A. Noseworthy, MD
though these traditional vitals will almost certainly remain a cornerstone of medical Michael J. Ackerman, MD,
practice, a wealth of readily available biometric data, facilitated by mobile health PhD
technologies, is transforming age-old approaches to assessment and monitoring in
both health and disease. As such, it appears increasingly likely that novel vital signs
will emerge from the current precision medicine revolution.
In the recent past, many new vital signs, ranging from subjective pain scales to
oxygen saturation to health literacy, have been proposed. Although each has some
merit, most provide redundant information and fail to meet the benchmark of a
true vital sign (ie, a rapid, objective, and quantifiable assessment of life-sustaining
function[s]).
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Until recently, the heart rate–corrected QT interval (QTc), which represents a

dynamic measurement of the time required to reset the heart’s electric system, fell
squarely into this latter category. However, with the present availability of cardiac
monitors equipped with automated QTc monitoring, and the more recent avail-
ability of Food and Drug Administration (FDA)–approved consumer mobile ECG
devices that appear capable of accurately detecting QTc prolongation (reported
sensitivity and specificity for a QTc >500 ms of 64% and 97%, respectively)1 in
settings where obtaining a traditional 12-lead ECG is simply not feasible or fiscally
possible, the technology to enable the QTc to enter the vital sign debate is finally
emerging.
To this end, a prolonged QTc, defined as a QTc value >450 ms in males and
>460 ms in females measured preferably in lead II or V5 on a standard 12-lead
ECG, predisposes to functional reentry, torsades de pointes, and sudden cardiac
death (SCD), and represents a widely accepted, easily measured, and quantifiable
risk factor for adverse outcomes.2,3 An otherwise unexplained baseline QTc >500
ms should prompt clinical suspicion for the possible presence of a potentially le-
thal, highly treatable condition known as congenital long-QT syndrome (LQTS).
In addition, acute QTc increases (ie, ΔQTc >60 ms) are indicative of the exagger-
ated QTc response that accompanies increased risk of torsades de pointes/SCD in
The opinions expressed in this article are
drug-induced LQTS.3,4 It is interesting to note that even modest QTc prolongation, not necessarily those of the editors or
perhaps mediated by elevated sympathetic tone, subclinical atherosclerosis, and of the American Heart Association.
electrolyte/metabolic abnormalities, is associated with an increased risk of cardio- Key Words:  arrhythmias, cardiac
vascular events, stroke, and all-cause mortality, often independent of traditional ◼ artificial intelligence ◼ death, sudden,
cardiac ◼ electrocardiography ◼ long
risk factors, in a variety of patient populations.2 QT syndrome ◼ vital signs
Collectively, this body of evidence illustrates that a prolonged QTc value,
© 2019 American Heart Association, Inc.
whether secondary to genetics, drugs, electrolyte perturbations, or systemic dis-
ease, represents a critical barometer of the heart’s electric system capable of https://www.ahajournals.org/journal/circ

Circulation. 2019;139:2711–2713. DOI: 10.1161/CIRCULATIONAHA.119.039598 June 11, 2019 2711

 Giudicessi et al
identifying potentially at-risk individuals. Therefore, as
FRAME OF REFERENCE
the technological barriers to accurate QTc assessment
continue to fall, we can now consider what line(s) of
evidence, if any, support consideration of the QTc as
a vital sign.
First, the incidence of congenital LQTS (≈1:2500 in-
dividuals) exceeds many of the genetic disorders con-
tained on the Health Resources and Services Admin-
istration’s Recommended Universal Screening Panel.5
Because congenital LQTS is not ordinarily detected in
the absence of symptoms (ie, syncope or SCD) and an
inexpensive/effective therapy (β-blockers) exists, the
only barrier for universal screening consideration is an
accurate and cost-effective screening test. Although
universal 12-lead ECG screening of newborns and
children for SCD-predisposing disorders has proved
to be efficacious and cost-effective in countries with
nationalized health systems (ie, Japan and Italy), this
has not been adopted globally. Treating the QTc as
a distinct vital sign first assessed during infancy and
then monitored continuously throughout life, likely
using augmented human intelligence–aided mobile
ECG devices rather than comparatively more expen-
sive formal 12-lead ECGs, may finally pave the way to
cost-effective universal screening for congenital LQTS
in the United States.
Second, medical errors represent the third most
common cause of death in the United States, and un-
recognized drug-drug interactions are among the most
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common culprits. More than 100 FDA-approved drugs
marketed in the United States, affecting all disciplines
of medicine, have either QTc-prolonging or torsado-
genic potential.4 Furthermore, serious QTc-related safe-
ty concerns identified through postmarketing surveil-
lance or FDA-mandated thorough QTc studies remain
a common reason for drug withdrawal and the failure
of otherwise promising new drugs to reach the market,
respectively.
Although documented cardiac arrest/SCD second-
ary to drug-induced LQTS/torsades de pointes is rare,
awareness of and access to tools capable of identifying
those patients at highest risk for this catastrophic, but
preventable, event is lacking. For potentially torsado-
genic drugs, notably the class III antiarrhythmics dofeti-
lide and sotalol, these issues led the FDA to mandate
continuous QTc monitoring during drug loading and
recommend periodic outpatient ECG monitoring there-
after. As such, the QTc already functions as a de facto
vital sign for those on class III antiarrhythmics that al-
lows for the efficient, but costly, identification of pa-
tients where the known risk of torsades de pointes/SCD
far outweighs therapeutic benefit.
With an increasingly medically complex patient pop-
ulation, the number of patients receiving ≥1 QTc-pro-
longing medication, many with additional underlying
QT-aggravating risk factors, is rising. Given the ability of
2712 June 11, 2019
QT Interval as a Vital Sign?
mobile ECG devices to detect progressive QTc prolonga-
tion, there is no reason to believe the safety consider-
ations behind class III antiarrhythmic monitoring could
not be extended to other QTc-prolonging medications
such as methadone in the future. With cost and pa-
tient preference driving the shift of inpatient services
into ambulatory settings, treating the QTc as a routinely
assessed vital sign represents a potential means of en-
hancing patient safety and individualizing patient care
by (1) facilitating the safe outpatient initiation of par-
ticularly torsadogenic drugs, (2) preventing life-threat-
ening QTc polypharmacy in patients with multiple co-
morbidities, and (3) providing an avenue for otherwise
clinically efficacious drugs, sidelined by QT safety issues,
to safely enter the market.
Last, multiple lines of evidence suggest that mod-
est QTc prolongation in middle-aged and older adults
may serve as an early marker for serious cardiovascular
events and death.2 Although the precise mechanism(s)
underlying this phenomenon remains unclear, consis-
tent monitoring of the QTc throughout an individual’s
lifespan, akin to existing vital signs, may enhance exist-
ing risk-stratification strategies and aid in the identi-
fication of a high-risk subset of patients that requires
closer scrutiny for evidence of subclinical cardiovascu-
lar disease.
With a robust means of rapidly, objectively, and
quantifiably monitoring ECG parameters, independent
of standard 12-lead ECGs, already at our fingertips or
on our wrists, now is the time to consider how to best
expand and use this exciting technology.1 Although
current FDA-approved single-lead mobile ECG devices
do not record leads II or V5 or allow for the manual se-
lection of the lead that best shows the QT interval, the
QTc as a potentially life-saving vital sign may still be a
great place to start.
ARTICLE INFORMATION
Correspondence
Michael J. Ackerman, MD, PhD, Mayo Clinic Windland Smith Rice Sudden
Death Genomics Laboratory, Guggenheim 501, Mayo Clinic, Rochester, MN
55905. Email ackerman.michael@mayo.edu
Affiliations
Department of Cardiovascular Medicine, Clinician-Investigator Training Program
(J.R.G.), Department of Cardiovascular Medicine, Division of Heart Rhythm Ser-
vices (P.A.N., M.J.A.), Department of Pediatric and Adolescent Medicine, Divi-
sion of Pediatric Cardiology (M.J.A.), Department of Molecular Pharmacology
and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics
Laboratory (M.J.A.), Mayo Clinic, Rochester, MN.
Disclosures
Dr Giudicessi has no conflicts to disclose. Dr Noseworthy has a potential equity/
royalty relationship (without remuneration so far) with AliveCor. Dr Ackerman is
a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invi-
tae, Medtronic, MyoKardia, and St Jude Medical, and has potential equity/roy-
alty relationships (without remuneration so far) with AliveCor, Blue Ox Health,
and Stemonix. However, no commercial entities participated in this study.
Circulation. 2019;139:2711–2713. DOI: 10.1161/CIRCULATIONAHA.119.039598
 Giudicessi et al
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QT Interval as a Vital Sign?
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