JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
24, 2019
ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
EDITORIAL COMMENT
Electrolytes and the ECG Intervals
Big Data and Little Insight*
Brian Olshansky, MD,a Syamal K. Bhattacharya, PHDb
O bservations connecting electrolyte anoma-
lies to the genesis of cardiac arrhythmias
date to the 1880s, when A.G. Mayer noted
changes in jellyfish contractions by varying solutions
in electrolyte baths in which they were immersed.
Development of the string galvanometer and subse-
quent advancements in electrocardiogram (ECG)
recordings led to observations in humans that auto-
maticity, cardiac conduction and repolarization
depend on serum electrolyte concentrations. Today,
electrolyte abnormalities, including hypokalemia,
hyperkalemia, hypocalcemia, hypermagnesemia,
and others, have well-known effects on ECG record-
ings and can cause serious rhythm disturbances, and
death. However, no large, systematic study relates
electrolyte concentrations to specific ECG intervals
in the general population, until now.
SEE PAGE 3118
In this issue of the Journal, Noordam et al. (1)
report a robust meta-analysis evaluating associa-
tions between serum electrolyte concentrations and
ECG intervals. In this consensus-building, multi-
centered, global assessment of 153,014 individuals
from 38 study groups of 33 cohorts in 5 distinct an-
cestries, RR, QT, QRS, JT, and PR intervals were
þ2 þ2 þ þ
associated with variations in Ca , Mg K , and Na
*Editorials published in the Journal of the American College of Cardiology
reflect the views of the authors and do not necessarily represent the
views of JACC or the American College of Cardiology.
From the aDivision of Cardiology, Department of Medicine, University of
b
Iowa Hospitals and Clinics, Iowa City, Iowa; and the University of
Tennessee Health Science Center, Memphis, Tennessee. Dr. Olshansky
has served as a speaker for Lundbeck; has served as a consultant for
Boehringer Ingelheim and Respironics; has served on the Data Safety
Monitoring Board for Amarin; and has received honoraria from Lund-
beck, Boehringer Ingelheim, Respironics, and Amarin. Dr. Bhattacharya
has reported that he has no relationships relevant to the contents of this
paper to disclose.
ISSN 0735-1097/$36.00
VOL. 73, NO.
concentrations stratified by quintiles and adjusted for
confounders including hypertension (drug user vs.
nonuser), sex, and ancestry. Upon examining 20
distinct ECG-electrolyte associations, the strongest
link was “clinically relevant” (>5 ms) QT prolongation
at lowest Ca þ2 concentrations (2% of the population).
QT prolongation also occurred with higher Mgþ2
concentrations. Apparent K þ concentration effects
were driven primarily by antihypertensive drugs. Naþ
concentration was associated with small changes in
QRS duration.
For the first time, “big data” from large, diverse
populations associated electrolyte concentrations to
ECG intervals. Notwithstanding numerous intriguing
relationships, on close inspection, these data raise
more questions than provide answers.
Although some results are anticipatory (e.g., QT
lengthening with lower Ca þ2), how electrolyte con-
centrations affect ECG intervals remains uncertain.
Associations do not prove causality and even if a
causal relationship exists, what is it? Electrolyte
concentrations can modulate multiple cardiac chan-
nels but each channel type may have discrepant, or
even competing, physiological effects on depolariza-
tion and repolarization.
Consider that increasing Mgþ2 concentrations were
associated with increasing QT intervals. Should we
worry? Mgþ2 concentrations were not associated with
changes in PR intervals as may be expected. Why is
this? Intriguingly, changes in K þ (after data adjust-
ment) were not associated with ECG abnormalities.
Observed differences in ECG intervals between men
and women were not explained by electrolyte con-
centrations alone but, then, what are the explana-
tions? Do putative associations provide new insights?
We are not so sure.
The extremely large size of this study is undoubt-
edly a strength but there are inescapable weaknesses.
With big data like these, statistically significant
https://doi.org/10.1016/j.jacc.2019.04.027
JACC VOL. 73, NO. 24, 2019
JUNE 25, 2019:3132–4
changes can be detected with exceedingly small dif-
ferences in observed ECG intervals or electrolyte
concentrations but small differences in QT interval
may be devoid of any clinical or physiological mean-
ing. This crucial point pertains to overinterpreting
results when exceedingly small differences in very
large populations appear significant. Big data do not
necessarily provide big answers to critical, chal-
lenging, pathophysiological conundrums.
At extremes, the relationship of ECG intervals to
K þ concentrations is nonlinear. This may be true for
other electrolytes as well, especially at extremes, but
what about in the general population? A beta coeffi-
cient, suggesting degrees of association, may help
understand what ranges are important, or critical, but
differences may become manifest only at outlying
values. Moreover, these data cannot help extrapolate
relationships of varying electrolyte levels to ECG in-
tervals for any given individual.
The authors attempt to adjust for confounding
variables but do not ascertain synergistic, or coun-
teractive, effects of one electrolyte with another. Any
level at which relevant interactions occur remains
uncertain. Higher Mg þ2 and lower Ca þ2 levels each
prolong the QT but what is the combined effect? Is all
QT prolongation problematic? Mgþ2 may increase QT
intervals but prevent torsades de pointes. Why? Big
data alone are not big enough to answer these
questions.
It remains unclear what to do with these data.
Small changes have not been shown to have an
adverse or beneficial effect. Any putative relationship
of intervals to outcomes is extrapolated from other
data and, in so doing, provide a dangerous precedent.
What do these data tell us about populations at large?
What interventions make a difference? Answers to
these questions are, by no means, obvious.
No data presented here implicate relationships
between lower Caþ2 concentrations, for example, and
adverse outcomes. Perhaps, a specific genetic ab-
normality exists in which lower Ca þ2 concentrations
are associated with longer QT intervals and higher
risk for ventricular arrhythmias. Perhaps not. We
caution overinterpretation of data that implicate
slight lengthening in QT intervals as “clinically
relevant.”
Slight QT prolongation, by itself, may have no
specific meaning or prognostic value. Considering the
Food and Drug Administration 5-ms threshold for
regulatory concern following a “thorough QT/QTc
study” in healthy volunteers testing drugs that may
lengthen the QT interval has no specific applicability
here because no evidence implicates longer QT
Olshansky and Bhattacharya 3133
Electrolytes and the ECG
intervals related to elevated Mgþ2 levels alone, for
example, with outcomes or arrhythmias.
The ECG is, after all, a rather crude measure.
Repolarization, manifest by longer QT/JT intervals
alone may have little to do with 3-dimensional
directionality of repolarization and potential com-
plexities of arrhythmogenesis. Interval measurement
has nothing to do directly with atrial repolarization,
automaticity or conduction disturbances. Data
relating electrolytes to ambient arrhythmias may be
more valuable.
This study does not help discern which patient
with a specific electrolyte concentration–QT interval
relationship would be a good candidate for a drug that
affects the QT interval. Generally, drugs that lengthen
QT intervals and that can cause torsade de pointes
affect the IKr (HERG) channel. However, while higher
Mgþ2 concentrations were associated with longer QT
intervals, Mg þ2 may prevent, rather than cause,
torsade de pointes by blocking the HERG channel.
While antihypertensive medications in this study
may influence the QT interval, without knowing
specifics about the drugs involved, clinically relevant
inferences cannot be drawn about any risk these
drugs may cause.
It will be important to gain deeper insight into
mechanistic relationships between fluctuations
within relatively normal electrolyte concentrations
producing minor changes in ECG intervals as they
relate to important measurable outcomes. Under-
standing such associations would further enhance
our understanding of how to integrate this informa-
tion into patient care and whether to consider specific
drug restrictions in those with slightly prolonged QT
intervals, for example.
Moving forward, there may be specific information
more telling on the ECG that cannot be determined by
interval measurement alone. As artificial intelligence
is strategically applied to ECGs, it may be possible to
detect the imprint of electrolyte concentrations and
determine whether effects are good or bad. For
example, Mgþ2 may lengthen the QT interval but
transform T waves with a specific morphologic
configuration. The ECG may be rich with undetectable
information to date. Artificial intelligence might help
distinguish interrelationships between genomics,
drugs, electrolytes, gender and outcomes.
Data from Noordam et al. (1) provide an exciting
glimpse into relationships between electrolyte con-
centrations and ECG intervals in the general popula-
tion. However, big data do not necessarily provide big
insights leaving much to unravel about clinical
outcomes, risk assessment, mechanisms, causal
3134 Olshansky and Bhattacharya JACC VOL. 73, NO. 24, 2019

Electrolytes and the ECG JUNE 25, 2019:3132–4

relationships, and interventions. We congratulate the

authors for providing this novel interplay between ADDRESS FOR CORRESPONDENCE: Dr. Brian
electrolytes and ECG intervals suggesting proposed Olshansky, Division of Cardiology, Department of
dynamic relationships, but caution against Medicine, University of Iowa Hospitals, 200
overinterpretation of this information for potential Hawkins Drive, Iowa City, Iowa 52242. E-mail:
clinical applications. brian-olshansky@uiowa.edu. Twitter: @uihealthcare.

REFERENCE

1. Noordam R, Young WJ, Salman R, et al. Effects of

calcium, magnesium, and potassium concentra- KEY WORDS cohort studies,
tions on ventricular repolarization in unselected electrocardiographic intervals, electrolytes,
individuals. J Am Coll Cardiol 2019;73:3118–31. epidemiology, meta-analysis