Physiological Variations, Environmental Factors, and Genetic Modifications in Inherited LQT Syndromes∗

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 65, NO. 4, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacc.2014.11.014

EDITORIAL COMMENT

Physiological Variations, Environmental Factors, and Genetic Modifications in Inherited LQT Syndromes* Robert J. Myerburg, MD

V

ariations in clinical expression of genetically

primary defect. Even though LQTS risk modifiers that

based disorders are common, especially for

may enhance (5) or decrease (6) intensity of expres-

syndromes characterized by complex physi-

sion have been reported, progress has been slow, in

ological pathways. Although not unique to the

part because expression is also modulated by various

inherited long QT syndromes (LQTS), patterns of

physiological fluctuations, drug and electrolyte in-

complex interactions are particularly striking in fam-

fluences, and environmental factors. For example,

ilies in which multiple relatives carry an LQT variant

very early in the development of insights into LQTS,

identified in a proband (1–3), creating challenges for

the role of sympathetic nervous system activity in

clinicians, electrophysiologists, and clinical geneti-

expression modulation became evident, leading to

cists. Variations in expression of both the presence

left stellate ganglionectomy as the first effective

and extent of QT prolongation (Figure 1, Level 1) as

therapy in 1971 (7), subsequently followed by beta-

well as clinical events (Figure 1, Level 2) (4) manifest

blocker therapy when that class of drugs became

among carriers of LQTS mutations in large family

available.

cohorts. Because a major goal of genetic testing is

Other

factors

modifying

clinical

expression,

risk identification and profiling of relatives of pro-

derived from physiology, pharmacology, and elec-

bands, it follows that variable expression limits clin-

trolyte balance, continued to emerge, with physicians

ical decision making in asymptomatic carriers.

becoming familiar with interactions with drugs that

Investigators have long sought identifiable modi-

influence cardiac repolarizing currents, serum potas-

fiers of risk in individual LQTS carriers. The vague

sium and magnesium levels, and permissible in-

and physiologically imprecise notion of “incomplete

tensity of exercise. Drug exposures and serum

penetrance” was the first explanation of this phe-

electrolyte variations can interact with defective ion

nomenon, but that idea generated only hypothetical

channel control of membrane currents in patients

pathways. The concept of “modifier genes” for LQTS

with LQTS. For instance, although severe hypokale-

expression emerged early after the discovery of the

mia alone can lengthen the QT interval sufficiently

primary variants associated with LQTS. The theory:

to cause ventricular arrhythmias, lesser degrees of

single-nucleotide polymorphisms or mutations that

hypokalemia or even low normal serum potassium

were clinically unimportant alone interacted with

levels can elicit such effects when associated with

disease-causing mutations to alter expression of the

an inherited blunting of transmembrane potassium currents. The basis for this phenomenon lies in the

*Editorials published in the Journal of the American College of Cardiology

general

reflect the views of the authors and do not necessarily represent the

potassium levels and reduced current density in some

views of JACC or the American College of Cardiology.

potassium channel species (8).

From the Division of Cardiology, University of Miami Miller School of Medicine, Miami, Florida. Dr. Myerburg is supported in part by the American Heart Association Chair in Cardiovascular Research at the University of Miami Miller School of Medicine. Dr. Myerburg has reported

relationship

between

low

extracellular

SEE PAGE 367

Against this background of possible molecular and

that he has no relationships relevant to the contents of this paper to

physiological interactions with LQTS-causing muta-

disclose.

tions, the use of the term “genetic modification” is

376

Myerburg

JACC VOL. 65, NO. 4, 2015 FEBRUARY 3, 2015:375–7

Modification Genetics in LQT Syndrome

F I G U R E 1 Variable Expression in Inherited Long QT Syndrome

LQT Gene (+) cohort

Q-T MODIFIERS (Electrolytes, drugs, genetic variants)

EXPRESSION LEVEL 1

LQT Phenotype (-)

LQT Phenotype (+)

ARRHYTHMOGENIC MODIFIERS (Ca effects; autonomic modifiers, drugs and electrolytes, exogenous influences, genetic variants)

EXPRESSION LEVEL 2

Arrhythmia phenotype (+)

2+

Arrhythmia phenotype (-)

Arrhythmia phenotype (+)

Arrhythmia phenotype (-)

Clinical expression of long QT syndrome (LQTS) can be viewed as a multistage expression algorithm. Level 1 in gene-positive subjects refers to whether and what extent the corrected QT interval (QTc) lengthens. Level 2 refers to expression variability of clinical events, based upon physiological, environmental, and genetic modifiers. This feature of LQTS reflects the difficulty in decision making in gene-positive carriers, with and without baseline QTc prolongation. Modified with permission from Myerburg and Castellanos (4).

suggested as a generalization with dual implications:

of sympathetic activity. Because risk in the LQT1

1) alteration of primary genetic effects on ion chan-

variant has been associated with exercise and other

nels by interaction with a second genetic variant; and

forms of sympathetic stimulation, it was intuitive

2) modification of the expression of a disease-causing

that increased sympathetic activity should be asso-

mutation

its

ciated with higher risk. Accordingly, the investigators

pathway of expression. The report by Porta et al. (9)

looked at noninvasive surrogates for sympathetic

in this issue of the Journal integrates both of these

activity

implications: the general sympathetic influence on

demonstrated less QT variability in the low-frequency

by

nongenetic

factors

influencing

and

paradoxically

observed

that

SMCs

expression in LQTS type 1 (LQT1) paired with the

range compared with AMCs. Thus, greater sympa-

possibility of genetic influences affecting responses

thetic activity and less parasympathetic activity

to a physiological modifier of expression. The

appear protective in this population, in contrast to

extraordinarily well-studied South African founder

other disease states. This unique observation raises

genotype (KCNQ1 A341V), characterized by an epide-

questions about our concepts of pathophysiology for

miologically and clinically powerful phenotype, was

LQT1 and holds implications for risk profiling, at least

examined to evaluate the role of sympathetic activity

for carriers of A341V.

in modifying risk in this LQT1 population because

One must remain cautious, however, about 3

LQT1 is particularly sensitive to sympathetic activity.

possibilities. The first is whether the previously

Nearly 80% of A341V carriers become symptomatic by

described protective effect of parasympathetic activ-

40 years of age, compared with approximately 30%

ity, even if reduced, overrides a potentially adverse

among other KCNQ1 variants (10,11). The researchers

effect of increased sympathetic drive, giving the

previously reported that asymptomatic mutation

appearance of sympathetic protection. This contrasts

carriers (AMCs) of LQT1 variants are more likely to

with sympathetic drive being uniquely protective.

have lower heart rates, lower baroreceptor sensi-

This study’s design does not permit this distinc-

tivity, and a lesser degree of heart rate decrease at the

tion, although the QT parameter used suggests

end of exercise than symptomatic mutation carriers

independence.

(SMCs). These data suggest a protective effect of

The second concern focuses on whether the nature

reduced vagal reflexes but do not account for the role

of this specific mutation allows generalization to

Myerburg

JACC VOL. 65, NO. 4, 2015 FEBRUARY 3, 2015:375–7

Modification Genetics in LQT Syndrome

other variants of LQT1 or other LQT subsets. Because

both carriers and noncarriers of A341V had similar

A341V is properly characterized as a “hot spot,” with

wide distributions of baroreflex sensitivity (12), inti-

extraordinarily

wonders

mating that the pattern of parasympathetic respon-

whether the negative association between clinical

siveness is genetically driven, even though the

events and increased sympathetic activity might be

distribution of responses are continuous, rather than

unique to this population. Further studies that

dichotomous (9). Nonetheless, if such variants are

include other variants associated with LQT1, and

identified, they could contribute to better risk

possibly A341V from non–South African subjects, as

profiling among A341V carriers, and perhaps other

was done in prior parasympathetic studies, are

variants. Stated another way, there appear to be

high

event

rates,

one

needed to determine whether this is a general

modifier genes affecting a physiological pathway

association.

generally known to be associated with risk in LQTS, in

The third point relates to the notion that the

which the response to the autonomic stimulus is

sympathetic responses observed in this population

modified by a separate genetic influence. This pro-

are genetically driven. The possibilities that genetic

vides a reasonable direction for future studies,

variants affecting autonomic nervous system ex-

focusing on individual risk prediction by modification

pression interact in a complex pathway with the LQT

genetics targeting expression of influences external

myocardial line, or conversely that another variant

to the primary QT defect.

alters ion channel response to sympathetic stimulation, are considerations of interest. These remain

REPRINT REQUESTS AND CORRESPONDENCE : Dr.

hypothetical because the researchers have not yet

Robert J. Myerburg, Division of Cardiology (D-39),

identified

the

University of Miami Miller School of Medicine, P. O.

observed autonomic response. A rationale for their

Box 016960, Miami, Florida 33101. E-mail: rmyerbur@

concept comes from previous studies suggesting that

med.miami.edu.

genetic

variants

associated

with

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KEY WORDS autonomic nervous system,

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syndrome type 1. J Am Coll Cardiol 2015;65: 367–74.

genetic modifiers, long QT syndrome, QT variability, variable expression

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