Epinephrine infusion in the evaluation of unexplained cardiac arrest

Epinephrine Infusion in the Evaluation of Unexplained
Cardiac Arrest and Familial Sudden Death
From the Cardiac Arrest Survivors With Preserved
Ejection Fraction Registry
Andrew D. Krahn, MD; Jeffrey S. Healey, MD; Vijay S. Chauhan, MD; David H. Birnie, MBBS;
Jean Champagne, MD; Shubhayan Sanatani, MD; Kamran Ahmad, MD; Emily Ballantyne, BSc;
Brenda Gerull, MD, PhD; Raymond Yee, MD; Allan C. Skanes, MD; Lorne J. Gula, MD;
Peter Leong-Sit, MD; George J. Klein, MD; Michael H. Gollob, MD;
Christopher S. Simpson, MD; Mario Talajic, MD; Martin Gardner, MD
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Background—Epinephrine infusion may unmask latent genetic conditions associated with cardiac arrest, including longQT syndrome and catecholaminergic polymorphic ventricular tachycardia (VT).
Methods and Results—Patients with unexplained cardiac arrest (normal left ventricular function and QT interval) and
selected family members from the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) registry
underwent epinephrine challenge at doses of 0.05, 0.10, and 0.20 μg/kg per minute. A test was considered positive for longQT syndrome if the absolute QT interval prolonged by ≥30 ms at 0.10 μg/kg per minute and borderline if QT prolongation
was 1 to 29 ms. Catecholaminergic polymorphic VT was diagnosed if epinephrine provoked ≥3 beats of polymorphic or
bidirectional VT and borderline if polymorphic couplets, premature ventricular contractions, or nonsustained monomorphic
VT was induced. Epinephrine infusion was performed in 170 patients (age, 42±16 years; 49% men), including 98 patients
with unexplained cardiac arrest. Testing was positive for long-QT syndrome in 31 patients (18%) and borderline in 24
patients (14%). Exercise testing provoked an abnormal QT response in 42% of tested patients with a positive epinephrine
response. Testing for catecholaminergic polymorphic VT was positive in 7% and borderline in 5%. Targeted genetic testing
of abnormal patients was positive in 17% of long-QT syndrome patients and 13% of catecholaminergic polymorphic VT
patients.
Conclusions—Epinephrine challenge provoked abnormalities in a substantial proportion of patients, most commonly a
prolonged QT interval. Exercise and genetic testing replicated the diagnosis suggested by the epinephrine response
in a small proportion of patients. Epinephrine infusion combined with exercise testing and targeted genetic testing is
recommended in the workup of suspected familial sudden death syndromes.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00292032.
(Circ Arrhythm Electrophysiol. 2012;5:933-940.)
Key Words: catecholaminergic polymorphic ventricular tachycardia ◼ diagnosis ◼ long-QT syndrome
◼ genetic testing
P
rovocative testing with epinephrine infusion has become
routine for the evaluation of familial sudden death and
unexplained cardiac arrest (UCA).1–5 The primary purpose is
to unmask long-QT syndrome (LQTS),6–9 although it is also
used to unmask catecholaminergic polymorphic ventricular
tachycardia (CPVT).4,5,10 Previous testing has largely focused
on genetically characterized patients who subsequently
underwent testing, suggesting excellent test performance in
the detection of type 1 LQTS6,8,9 in patients with genetically
proven disease. The usefulness of the test is best assessed
in an undiagnosed population that is at risk for the target
disorder. We evaluated the yield of epinephrine infusion and
Received February 29, 2012; accepted August 20, 2012.
From the University of British Columbia (A.D.K.), Vancouver, BC; Population Health Research Institute, McMaster University (J.S.H.), Hamilton,
ON; University Health Network (V.S.C.), Toronto, Canada; University of Ottawa Heart Institute (D.H.B., M.H.G.), Ottawa, ON; Quebec Heart Institute
(J.C.), Laval Hospital, Quebec City, PQ; BC Children’s Hospital (S.S.), Vancouver, British Columbia, Vancouver, BC; St Michael’s Hospital (K.A.),
Toronto, Canada; University of Western Ontario (E.B., R.Y., A.C.S., L.J.G., P.L-S., G.J.K.), London, ON; Libin Cardiovascular Institute of Alberta (B.G.),
University of Calgary, Calgary, AB; Queen’s University (C.S.S.), Kingston, ON; Montreal Heart Institute (M.T.), Montreal, PQ; and QEII Health Sciences
Center (M.G.), Halifax, NS, Canada.
The online-only Data Supplement is available at http://circep.ahajournals.org/lookup/suppl/doi:10.1161/CIRCEP.112.973230/-/DC1.
Correspondence to Andrew Krahn, MD, Arrhythmia Service, 9th Floor, Gordon & Leslie Diamond Health Care Centre, 2775 Laurel St, Vancouver, BC,
V5Z 1M9 Canada. E-mail [email protected]
© 2012 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org
933
DOI: 10.1161/CIRCEP.112.973230
934 Circ Arrhythm Electrophysiol October 2012
its exercise and genetic correlates in a national registry of
UCA and familial sudden death.
Editorial see p 879
Clinical Perspective on p 940
Methods
Patients
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Details of the Cardiac Arrest Survivors with Preserved Ejection
Fraction Registry (CASPER) registry have previously been reported.5 Briefly, CASPER is a national registry in 11 centers that examines phenotype-genotype correlation and assesses test performance
in familial sudden death and UCA. Cardiac arrest patients were
eligible for enrollment if they had experienced an UCA with documented cardiovascular collapse, with ventricular tachycardia (VT) or
fibrillation requiring direct current (DC) cardioversion or defibrillation to restore sinus rhythm. Follow-up testing demonstrated normal
left ventricular function (left ventricular ejection fraction ≥50%) and
normal coronary arteries.4 Patients were permitted to have transient
left ventricular dysfunction or QT prolongation immediately after
the cardiac arrest if these resolved promptly. Additional study groups
described below include cardiac arrest patient’s first-degree relatives
and first-degree relatives of unexplained sudden death victims. In total, 4 populations underwent epinephrine infusion: (1) cardiac arrest
probands as described above; (2) first-degree relatives of the cardiac
arrest proband; (3) first-degree relatives of an unexplained sudden
cardiac death (SCD) before the age of 60 with a negative autopsy,
presumed arrhythmic; and (4) syncope with documented polymorphic ventricular tachycardia (PMVT).
Investigators and coordinators performed a consultation/assessment to determine whether reversible causes, including drug overdose or a proarrhythmic effect, were present or reviewed the medical
record when the arrest was no longer acute. Patients were excluded if
men had a resting QTc >460 ms and women had a QTc >480 ms11,12
or if a reversible cause of cardiac arrest such as marked hypokalemia
or drug overdose was present. Patients were also excluded if any coronary artery had stenosis >50% or had anomalous coronary arteries,
if imaging demonstrated evidence of hypertrophic cardiomyopathy, if
they experienced commotio cordis, if there was persistent ST-segment
elevation with ≥2 mm ST elevation in V1 and/or V2 (Brugada pattern),
or if they had hemodynamically stable sustained monomorphic VT
with a QRS morphology consistent with recognized forms of idiopathic VT.13 Patients were permitted to have transient left ventricular
dysfunction or QT prolongation immediately after the cardiac arrest
if these resolved promptly.
Patients included in the current analysis were enrolled in the CASPER
registry between January 2004 and June 2011 from 11 Canadian electrophysiology centers. All patients provided written i­nformed consent.
The protocol was approved by the Health Sciences Research Ethics
Board of the University of Western Ontario and at each center (www.
ClinicalTrials.gov NCT00292032—Registry of UCA).
Testing Procedures
Patients underwent evaluation as described in the previous published
algorithm, including noninvasive and invasive testing in cardiac arrest
probands and noninvasive testing in relatives. The extent of testing was
based on investigator discretion, taking into account the presentation/
trigger in the patient or family member, the findings from previous testing, and the residual index of suspicion. Epinephrine was typically carried out in a cardiac arrest survivor unless a diagnosis was previously
obtained. Family members underwent epinephrine infusion when a suspicion arose from other testing, either in their family proband or from
their resting or exercise ECGs. A small number of patients declined
testing because of the perceived risks (not quantified).
Epinephrine infusion was performed through a peripheral intravenous
line with continuous ECG monitoring. Intravenous epinephrine challenge was performed according to the Mayo Clinic (Ackerman) protocol
as previously described, with continuous monitoring at doses of 0.05,
0.10, and 0.20 μg/kg per minute.9 Twelve-lead ECGs were performed
at baseline and just before each dose increment. The infusion was discontinued if systolic blood pressure fell below 80 mm Hg, exceeded 200
mm Hg, if monitoring detected nonsustained VT or PMVT, >10 premature ventricular contractions/min or previously absent T-wave alternans,
or patient intolerance because of headache and nausea.7 If symptoms persisted after discontinuation, metoprolol 2.5 to 5 mg was administered intravenously over 1 minute. The QT interval and heart rate were measured
by the site investigator who was unaware of genetic findings at the end
of each 5-minute period, and the QTc was calculated using the Bazett
­formula.14 The end of the T wave was defined as the intersection of the
maximum downslope of the ST segment with the isoelectric line of the
TP segment.15 U waves were excluded from the measured QT interval.
Epinephrine infusion was considered positive for LQTS if the absolute QT prolonged by ≥30 ms at 0.10 μg/kg per minute and borderline if the QT prolongation was 0 to 29 ms (Figure 1).9 The test was
considered positive for CPVT if epinephrine provoked ≥3 beats of
polymorphic VT or bidirectional VT and borderline if polymorphic
couplets, premature ventricular contractions, or nonsustained monomorphic VT was induced (Figure 2).5,6,9,10
Figure 1. ECGs from a 17-year-old woman
whose brother died suddenly, with no anatomic cause of death identified at autopsy.
The baseline QT and QTc are unremarkable, but the absolute QT interval prolongs
by 60 ms during epinephrine infusion at
0.10 μg/kg per minute. Genetic testing was
negative for long-QT syndrome causative
mutations.
Krahn et al Epinephrine in Familial Sudden Death Assessment 935
Table 1. Baseline Characteristics of the Study Population
(n=170)
Age, y
41.6±16.0
Sex (% female)
86 (50.6%)
Patient type
Figure 2. ECGs from 2 cases of unexplained cardiac arrest with
epinephrine provocation of nonsustained bidirectional ventricular tachycardia in the upper panel and polymorphic ventricular
tachycardia in the lower panel. Both observations were considered a positive test for catecholaminergic polymorphic ventricular
tachycardia. Genetic testing was negative for RyR2 causative
mutations.
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Symptom-limited exercise testing was performed with a modified
or standard Bruce protocol. A positive exercise test for LQTS was
defined as an end-recovery QTc >455 ms based on a recently vali­
dated algorithm (4–6 minutes into recovery).16,17 Targeted genetic
testing was performed on the basis of phenotype detection after clinical testing was complete. Testing was accessed on the basis of clinical testing from commercial vendors (n=54; Familion-Transgenomic,
Omaha, NE, and GeneDx, Gaithersburg, MD; KCNQ1, KCNH2,
SCN5A, KCNE1, KCNE2, and additional genes based on generation of testing). Limited research testing assessed 8 patients, with 3
major genes in 3 patients (KCNQ1, KCNH2, SCN5A) and single
gene in 5 patients. Genomic DNA was isolated from blood lymphocytes and screened with direct sequencing performed on suspected
culprit genes.
Investigators were asked to review the entire patient record, including
the nature and context of symptoms, family history, and the results of
clinical and genetic testing, and render a working diagnosis and a qualitative descriptor of the strength of the diagnosis as definite, probable,
and possible based on the weight of the evidence. The working diagnosis could be revised over time based on events during follow-up, repeat
clinical or genetic testing, or determination of previously unrecognized
diagnoses such as early repolarization or short-QT syndrome. Testing of
family members of cardiac arrest victims was pursued after investigation of the index arrest patient was complete. This led to tailoring of
investigations based on the findings in cardiac arrest patients.
Statistics
Continuous variables were compared by use of a 2-tailed Student
t test, and χ2 test was used for categorical variables. Fisher exact
testing was performed when cell sizes were ≤5. Multiple continuous variables were compared using ANOVA. Test performance was
assessed with calculation of sensitivity, specificity, positive and
negative predictive values, and likelihood ratios. Statistical analysis
was performed using GraphPad Prism software version 5 for Mac
(La Jolla, CA) by the authors (A.K.). Analysis was not stratified by
Unexplained cardiac arrest proband
98 (57.7%)
First degree relative of unexplained cardiac arrest proband
35 (20.6%)
First degree relative of SCD victim*
30 (17.7%)
Syncope with polymorphic VT
7 (4.1%)
Maximum epinephrine dose
0.05 μg/kg per minute
4 (2.4%)
0.10 μg/kg per minute
2 (1.2%)
0.20 μg/kg per minute
164 (96.5%)
Genetic testing
Any testing
101 (59.4%)
LQTS genetic testing
61 (35.9%)
CPVT genetic testing
20 (11.8%)
Exercise test
107 (62.9%)
Normal
83 (72.9%)
Abnormal
29 (27.1%)
VT indicates ventricular tachycardia; LQTS, long QT syndrome; CPVT,
catecholaminergic polymorphic ventricular tachycardia.
*Two patients were included who were second-degree relatives whose
intervening relative was not available for testing.
patient group. P<0.05 was considered significant. All results are expressed as mean±SD.
Results
One hundred seventy patients underwent epinephrine infusion,
including 58% UCA patients, 21% UCA relatives, 18% SCD
relatives, and 4% patients with syncope and PMVT (Table 1).
The mean age was 41.6±16.0 years (range 14–79 years), and
86 patients were women (51%). The heart rate increased with
incremental epinephrine dosing, with minimal overall effect
in the absolute QT interval (Figure 3). The target maximum
dose of 0.20 μg/kg per minute was achieved in 164 patients
(96.5%), with 0.10 μg/kg per minute in 2 patients (1.2%)
and 0.05 μg/kg per minute in 4 patients (2.4%). Infusion
did not achieve the maximum dose because of nonsustained
Figure 3. Heart rate and QT-interval
changes during epinephrine infusion in 170
patients with unexplained cardiac arrest or
familial sudden death. bpm indicates beats
per minute.
936 Circ Arrhythm Electrophysiol October 2012
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ventricular arrhythmias in 3 patients, diagnostic QT changes
in 1, hypertension in 1, and chest discomfort in 1.
Based on the Ackerman protocol,6,9 the QT interval
increased by ≥30 ms in 31 patients (18%) and 10 to 25 ms in
24 patients (14%) at an infusion rate of 0.10 μg/kg per minute.
The QT interval increased by ≥30 ms in 6.5% of patients at
0.05 μg/kg per minute, 18% at 0.10 μg/kg per minute, and
21% at 0.20 μg/kg per minute (Figure 4).
In the 107 patients who had a correlated exercise test,
the end-recovery QTc was longer in the Ackerman-defined
positive epinephrine group compared with both borderline and negative patients (451±28 versus 432±28 versus
439±50 ms; ANOVA P=0.047; Figure 5, upper panel),
although the correlation between epinephrine ΔQT and
exercise end-recovery QTc was modest (R=0.20; P=0.042;
Figure 5, bottom panel). Sixty-five of the 107 patients had
normal findings on both tests. Using either the exercise test
or the epinephrine test as a gold standard for the diagnosis
of LQTS, both tests demonstrated good negative predictive
value but low positive predictive value (Table 2). Fiftyseven patients underwent genetic testing for LQTS that
included at least the 3 major genes (see Methods section),
and positive findings were restricted to patients with a positive epinephrine challenge, whose QT interval prolonged by
30 to 90 ms. A pathogenic mutation or variant of unknown
significance was found in only 4 of 20 epinephrine longQT positive patients tested (sensitivity 20%; Table 3). All 4
patients underwent exercise testing; all were abnormal with
an end-recovery QTc of 456 to 499 ms. Using a positive
stress test or genetic test as a gold standard, epinephrine
challenge had a sensitivity of 40%, specificity of 84%, positive predictive value of 0.5, and negative predictive value
of 0.78.
Of the 31 patients with a positive adrenaline challenge test,
integration of all baseline clinical testing, genetic studies, and
clinical follow-up led to a working diagnosis of long QT in
22 patients (71%). Of the remaining 9 patients, a working
diagnosis of idiopathic ventricular fibrillation (n=3) and normal (n=4) was based on lack of corroborating exercise and
genetic information (n=7), arrhythmogenic right ventricular
cardiomyopathy (n=1) based on genetic and imaging confirmation, and CPVT in 1 based on follow-up suppression of
recurrent PMVT treated with shocks from an implantable cardioverter defibrillator. Of the 41 patients with a working diagnosis of LQTS, a borderline or abnormal epinephrine response
was present in 35 patients (sensitivity including borderline
tests=85%). To evaluate the epinephrine response in patients
with no evidence or suspicion of long QT (no previous cardiac
arrest, normal resting QTc, negative stress test for long QT,
no known relative with long QT), the epinephrine result was
positive in 8 of 36 patients (22%).
Epinephrine challenge for CPVT was positive in 7% and
borderline in 5%. Among 18 epinephrine positive or borderline
patients for CPVT who underwent exercise testing, exercise
induced isolated premature ventricular contractions, couplets,
or bigeminy in 14 (sensitivity 78%) but nonsustained VT in
only 2. Twenty patients underwent genetic testing for CPVT
(RyR2 sequencing), and only 1 of 8 epinephrine positive
patients who had genetic testing had a mutation in the RyR2
gene (RyR2 M3978I, previously reported;10 sensitivity 13%).
Eleven of 12 patients with a working diagnosis of CPVT had
an abnormal or borderline response to epinephrine (n=7 and
4, respectively; 92% overall sensitivity). CPVT was diagnosed
during follow-up in a single patient with exercise-induced
syncope associated with nonsustained polymorphic VT, whose
adrenaline infusion and genetic testing were negative but
developed recurrent exercise-related PMVT associated with
implantable cardioverter defibrillator shocks that responded to
high-dose β-blockade.
The diagnostic yield of epinephrine infusion was not different when cardiac arrest patients were compared with the
familial sudden death comparator (all other patient groups
Figure 4. Individual QT changes during epinephrine infusion. The horizontal solid line reflects the published cutoff for a positive test of
≥30 ms. See text for discussion.
Krahn et al Epinephrine in Familial Sudden Death Assessment 937
Table 2. Test Performance Using Epinephrine and
Subsequently Exercise Testing as the Gold Standard for
Diagnosing LQTS
Epinephrine
positive
Epinephrine
negative
Total
Exercise positive
11
18
29
Exercise negative
13
65
78
24
83
107
Exercise to epinephrine
Sensitivity
Specificity
PPV
NPV
46%
78%
38%
83%
Gold standard
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Exercise
positive
Exercise
negative
Epinephrine positive
11
13
29
Epinephrine negative
18
65
78
24
83
107
Epinephrine to exercise
Sensitivity
Specificity
PPV
NPV
38%
83%
46%
78%
Gold standard
Figure 5. Comparison of epinephrine infusion for long-QT
syndrome with exercise test results. Mean QTc was longer in
patients with a positive epinephrine challenge (upper panel,
ANOVA P=0.047), and the correlation between epinephrine ΔQT
and exercise end-recovery QTc was modest (R=0.20; P=0.042,
bottom panel). See text for definitions of test interpretation.
combined, χ2 P=0.49 for LQTS, P=0.48 for CPVT; onlineonly Data Supplement Figure SI).
Discussion
This prospective multicenter study has demonstrated that epinephrine infusion provokes abnormalities in a large proportion
of patients with UCA or familial sudden death. These findings may suggest impaired repolarization reserve consistent
with LQTS, which is not borne out in the majority of cases
by manifest QT prolongation with exercise testing or conventional monogenic LQTS genetic findings. An ideal control
population was not studied, but the rate of QT prolongation is
LQTS indicates long QT syndrome; PPV, positive predictive value; NPV,
negative predictive value.
See text for discussion.
in keeping with the small number of control patients studied in
2 previous series using the Ackerman protocol.6,9
Previous studies have applied epinephrine infusion to
patients with genotyped LQTS or unaffected controls and
suggested excellent test performance in discriminating
LQTS patients from controls, and LQT1 as the dominantpositive response. These findings have stemmed from 2
high-profile research centers with a long history of LQTSrelated research. Although the Shimizu protocol differs
from the Ackerman protocol in the current study by using
bolus dosing,18,19 the findings are consistent with those by
Ackerman et al6,7,9 in both detection and genotype prediction
of LQTS. This may reflect a polarized population of study,
with clear evidence of phenotypic and genotypic LQTS or
healthy control status. These groups also assessed patients
with borderline and normal QT intervals who were gene
Table 3. Genetic Test Results in 4 Patients With Positive Epinephrine Challenge for LQTS
Baseline
QT/HR
0.10 μg/kg per min
QT/HR
Ventricular
Arrhythmias
LQTS
410 ms
65 bpm
450 ms
91 bpm
None
Pathogenic KCNH2 3256 ins
G 1086 Pro frameshift 32X
No exercise test
22/female
LQTS
420 ms
61 bpm
480 ms
85 bpm
PVCs
Pathogenic KCNH2 Arg
1007 His
End recovery QTc 482 ms
52/female
LQTS
440 ms
57 bpm
470 ms
67 bpm
None
KCNJ2 VUS Thr 400 Met
End recovery QTc 456 ms
15/male
LQTS
390 ms
69 bpm
480 ms
76 bpm
None
KCNQ1 VUS Pro 631 Arg
End recovery QTc 499 ms
Age/Sex
Diagnosis
29/male
Genetic Finding
Exercise Test Result
LQTS indicates long QT syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; VUS, variants of unknown significance; nsPMVT, nonsustained
polymorphic ventricular tachycardia; PVCs, frequent premature ventricular contractions; bpm, beats per minute; ICD, implantable cardioverter defibrillator.
A total of 61 patients had genetic testing for LQTS because of epinephrine infusion results, exercise testing, or clinical suspicion.
*This patient had polymorphic ventricular tachycardia with appropriate ICD shocks during follow-up, with subsequent positive genetic testing. See text for discussion.
938 Circ Arrhythm Electrophysiol October 2012
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carriers and found that the test was excellent at unmasking latent QT prolongation with paradoxical prolongation
of the absolute QT interval, with specificity >90%. The current study suggests that sensitivity is likely retained with
respect to the degree of QT prolongation in the 4 patients
with genetic evidence of LQTS, but calls into question the
specificity.6,8,9 This is particularly the case because firstdegree relatives had a similar response rate to the cardiac
arrest patients, who would have been expected to represent
an enriched sample with a higher positive yield of testing.
Assigning a working diagnosis of LQTS because of an isolated apparently abnormal epinephrine test by definition
forms a circular argument, diminishing the specificity of the
test because no other corroborating evidence is necessary to
arrive at the diagnosis and thus compare with an accepted
gold standard. Until a clear gold standard can be adopted
in conjunction with comprehensive testing of all patients,
the observations can only lead to the conclusion that epinephrine challenge provokes abnormalities that cannot be
validated by any of the putative gold standards.
The bolus infusion of Shimizu et al reported 100% specificity
of a QTc prolongation of ≥30 ms in identifying mutation
carriers.18,19 None of the 12 unaffected family members or
15 controls had QTc prolongation ≥30 ms. In a systematic
study of 24 healthy volunteers, Magnano et al20 did not detect
paradoxical QT prolongation or a QTc >600 ms at a low dose
of epinephrine or with isoproterenol but did see prominent U
waves and QT prolongation at higher doses of epinephrine
(0.20 μg/kg per minute). In contrast, the Ackerman protocol
use of paradoxical prolongation of the absolute QT interval of
≥30 ms was sensitive for LQTS (particularly LQT1) but was
less specific, seen in 6 of 27 controls (22%) in a preliminary
study and 18% of patients referred for LQTS evaluation who
were considered genotype negative.6,9 In that subset that most
closely resembles healthy controls (normal QTc, negative
stress test, and no previous cardiac arrest), the yield of
epinephrine challenge was 22%, consistent with the reports of
Ackerman et al.6 The latter group may represent an analogous
group to the current study population, although more than half
of the current population had experienced a cardiac arrest. This
suggests the need to study a larger number of healthy controls
to establish the specificity of the paradoxical response in an
at-risk population.
Multiple investigators have demonstrated the use of exercise testing in unmasking evidence of LQTS, particularly
when the resting QTc is not evidently prolonged.16,17,21–28
Exercise testing in the current study demonstrated a modest
correlation with adrenaline results, suggesting that neither test
is ideal in evaluating familial sudden death syndromes. This is
further hampered by genetic testing results, which were infrequently informative.
Epinephrine infusion provoked ventricular arrhythmias that suggested CPVT in a much smaller proportion of
patients. The likelihood of provoking ventricular arrhythmias
in healthy controls has been reported as very low, with no
arrhythmias noted in controls in 2 large series by Shimizu
et al,18,19 isolated premature ventricular contractions in 3 of 44
controls by Vyas et al,9 and bigeminy in 1 patient. These data
suggest that those patients with complex ectopy provoked
by epinephrine in the current study may in fact have latent
CPVT. These individuals clearly do not fall into the classic
definition of CPVT, which presents in a malignant fashion in
adolescence with a relatively high yield of detection of mutations in the RyR2 gene. A recent series that includes some of
the current patients has proposed that an adult-onset form of
CPVT may exist, with later presentation and a low yield of
genetic testing.10
Finally, test utility is best derived in a clearly defined
population with an evident gold standard. This was clearly the
case for epinephrine infusion for LQTS.6,7,9,18,19 Application of
the assessed test to an undiagnosed population that is at risk
for the target disorder then translates into real-world test utility
in the context of clinical uncertainty. The current study could
be interpreted to indicate prevalent impaired repolarization
reserve, but an alternate interpretation is that epinephrine
challenge is sensitive but not specific and that results should
be interpreted with caution in the absence of corroborating
evidence that the provoked abnormalities resonate with the
clinical presentation. Our interpretation of the current findings
is that exercise testing is a more physiological test to unmask
repolarization abnormalities than epinephrine infusion when
LQTS is suspected. The recognition that recovery is an ideal
period to detect QTc prolongation has simplified our previous
focus on the complex signals and acquisition artifact that is
often present during exercise. The pregenomic Schwartz score
was a first thoughtful attempt to quantify a continuum of
dose response. Replication of the current study in the whole
genome era with dual testing is predicted to demonstrate that
the term LQTS is indeed too simple and that a term such
as QT arrhythmia propensity index may better capture the
gradient of risk.
Larger-scale studies that include comprehensive genetic
testing, such as a whole genome approach, combined with rigorous phenotype characterization, extended follow-up, and a
large sample of healthy controls are necessary to determine the
implications of the current findings. In the interim, β-blockers
remain the mainstay of treatment for adrenergically mediated
disorders, which are generally well tolerated and effective.29,30
Whether this is the treatment of choice in the current population will require further study.
Limitations
The number of cases in this study was relatively small,
an inherent problem in studying uncommon diseases.
Nonetheless, this study is based on a prospective multicenter
experience, which is readily implemented in clinical practice.
ECG interpretation can be challenging in this context. This
study is limited by not capturing the subcomponents of the QT
interval such as the Tpeak-Tend interval, which has been reported
in previous studies and postulated to reflect dispersion of
refractoriness.18,19 Nonetheless, these same studies reported
similar prolongation of the QTend and QTpeak interval as well,
supporting the use of the summative QTend interval in the
current study. Other forms of adrenergic challenge were not
evaluated, such as isoproterenol challenge, which has been
proposed for CPVT.31 Finally, a comprehensive genetic screen
with extended follow-up was not performed on all patients.
Although this may have been ideal, genetic testing is of
Krahn et al Epinephrine in Familial Sudden Death Assessment 939
uncertain yield and is costly. Scarce genetic testing resources
are currently directed at families with multiple affected
members. Application of the results to a larger population is a
clear goal of the current study, which is currently underway.
A clear gold standard to test against is lacking in this realm,
because both genetic sequencing and exercise testing are
not without their own limitations. Further study in the entire
genome era combined with long-term follow-up may increase
the ability to discriminate between false-positive and truepositive epinephrine responses.
Conclusions
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Epinephrine challenge provoked abnormalities, suggesting
an arrhythmogenic substrate in a high proportion of patients,
most commonly QT prolongation. Exercise and genetic testing
infrequently replicated the basis of the epinephrine response.
These data suggest a potential incremental role for epinephrine challenge in detecting reduced repolarization reserve but
support the need for larger-scale assessment in a healthy control population to establish specificity and the utility of the
test. Epinephrine infusion combined with exercise testing and
targeted genetic testing is recommended in the workup of suspected familial sudden death syndromes.
Acknowledgments
We are indebted to the tireless work of the study coordinators and to
our patients who gladly participate to advance our understanding of
cardiac arrest and inherited arrhythmias.
Sources of Funding
Dr Krahn is a Career Investigator of the Heart and Stroke Foundation
of Ontario (CI6498). Dr Gollob is a Clinician Scientist of the Heart
and Stroke Foundation of Ontario. The study was supported by the
Heart and Stroke Foundation of Ontario (T6730) and an unrestricted
research grant from Boston Scientific.
Disclosures
None.
References
1. Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Robinson JL, Priori SG,
Benhorin J, Locati EH, Towbin JA, Keating MT, Lehmann MH, Hall WJ.
Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med.
1998;339:960–965.
2. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA. Mutations in the cardiac ryanodine receptor gene
(hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia.
Circulation. 2001;103:196–200.
3. Behr E, Wood DA, Wright M, Syrris P, Sheppard MN, Casey A, Davies
MJ, McKenna W; Sudden Arrhythmic Death Syndrome Steering Group.
Cardiological assessment of first-degree relatives in sudden arrhythmic
death syndrome. Lancet. 2003;362:1457–1459.
4. Krahn AD, Gollob M, Yee R, Gula LJ, Skanes AC, Walker BD, Klein GJ.
Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion. Circulation. 2005;112:2228–2234.
5. Krahn AD, Healey JS, Chauhan V, Birnie DH, Simpson CS, Champagne J,
Gardner M, Sanatani S, Exner DV, Klein GJ, Yee R, Skanes AC, Gula LJ,
Gollob MH. Systematic assessment of patients with unexplained cardiac
arrest: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry
(CASPER). Circulation. 2009;120:278–285.
6. Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen WK, Porter
CB. Epinephrine-induced QT interval prolongation: a gene-specific
paradoxical response in congenital long QT syndrome. Mayo Clin Proc.
2002;77:413–421.
7. Khositseth A, Hejlik J, Shen WK, Ackerman MJ. Epinephrine-induced
T-wave notching in congenital long QT syndrome. Heart Rhythm.
2005;2:141–146.
8. Noda T, Takaki H, Kurita T, Suyama K, Nagaya N, Taguchi A, Aihara
N, Kamakura S, Sunagawa K, Nakamura K, Ohe T, Horie M, Napolitano C, Towbin JA, Priori SG, Shimizu W. Gene-specific response of
dynamic ventricular repolarization to sympathetic stimulation in LQT1,
LQT2 and LQT3 forms of congenital long QT syndrome. Eur Heart J.
2002;23:975–983.
9. Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the
evaluation of congenital long-QT syndrome: diagnostic accuracy of the
paradoxical QT response. Circulation. 2006;113:1385–1392.
10. Sy RW, Gollob MH, Klein GJ, Yee R, Skanes AC, Gula LJ, Leong-Sit P,
Gow RM, Green MS, Birnie DH, Krahn AD. Arrhythmia characterization
and long-term outcomes in catecholaminergic polymorphic ventricular
tachycardia. Heart Rhythm. 2011;8:864–871.
11. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for
the long QT syndrome. An update. Circulation. 1993;88:782–784.
12. Swan H, Saarinen K, Kontula K, Toivonen L, Viitasalo M. Evaluation of
QT interval duration and dispersion and proposed clinical criteria in diagnosis of long QT syndrome in patients with a genetically uniform type of
LQT1. J Am Coll Cardiol. 1998;32:486–491.
13. Ainsworth CD, Skanes AC, Klein GJ, Gula LJ, Yee R, Krahn AD. Differentiating arrhythmogenic right ventricular cardiomyopathy from right
ventricular outflow tract ventricular tachycardia using multilead QRS duration and axis. Heart Rhythm. 2006;3:416–423.
14. Bazett HC. An analyisis of time relations of electrocardiograms. Heart.
1920;7:353–370.
15. Postema PG, De Jong JS, Van der Bilt IA, Wilde AA. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Heart
Rhythm. 2008;5:1015–1018.
16. Sy RW, van der Werf C, Chattha IS, Chockalingam P, Adler A, Healey JS,
Perrin M, Gollob MH, Skanes AC, Yee R, Gula LJ, Leong-Sit P, Viskin
S, Klein GJ, Wilde AA, Krahn AD. Derivation and validation of a simple
exercise-based algorithm for prediction of genetic testing in relatives of
LQTS probands. Circulation. 2011;124:2187–2194.
17. Chattha IS, Sy RW, Yee R, Gula LJ, Skanes AC, Klein GJ, Bennett MT,
Krahn AD. Utility of the recovery electrocardiogram after exercise: a novel indicator for the diagnosis and genotyping of long QT syndrome? Heart
Rhythm. 2010;7:906–911.
18. Shimizu W, Noda T, Takaki H, Nagaya N, Satomi K, Kurita T, Suyama K,
Aihara N, Sunagawa K, Echigo S, Miyamoto Y, Yoshimasa Y, Nakamura
K, Ohe T, Towbin JA, Priori SG, Kamakura S. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital
long QT syndrome. Heart Rhythm. 2004;1:276–283.
19. Shimizu W, Noda T, Takaki H, Kurita T, Nagaya N, Satomi K, Suyama
K, Aihara N, Kamakura S, Sunagawa K, Echigo S, Nakamura K, Ohe T,
Towbin JA, Napolitano C, Priori SG. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. J Am Coll
Cardiol. 2003;41:633–642.
20. Magnano AR, Talathoti N, Hallur R, Bloomfield DM, Garan H. Sympathomimetic infusion and cardiac repolarization: the normative effects of
epinephrine and isoproterenol in healthy subjects. J Cardiovasc Electrophysiol. 2006;17:983–989.
21. Kannankeril PJ, Harris PA, Norris KJ, Warsy I, Smith PD, Roden DM.
Rate-independent QT shortening during exercise in healthy subjects: terminal repolarization does not shorten with exercise. J Cardiovasc Electrophysiol. 2008;19:1284–1288.
22. Krahn AD, Klein GJ, Yee R. Hysteresis of the RT interval with exercise: a
new marker for the long-QT syndrome? Circulation. 1997;96:1551–1556.
23. Paavonen KJ, Swan H, Piippo K, Hokkanen L, Laitinen P, Viitasalo M,
Toivonen L, Kontula K. Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome. Heart.
2001;86:39–44.
24. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano
C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs
AH, Brink P, Wilde AA, Toivonen L, Zareba W, Robinson JL, Timothy
KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, Bloise R. Genotypephenotype correlation in the long-QT syndrome: gene-specific triggers for
life-threatening arrhythmias. Circulation. 2001;103:89–95.
25. Swan H, Toivonen L, Viitasalo M. Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome. Eur
Heart J. 1998;19:508–513.
940 Circ Arrhythm Electrophysiol October 2012
26. Sy RW, Chattha IS, Klein GJ, Gula LJ, Skanes AC, Yee R, Bennett MT, Krahn
AD. Repolarization dynamics during exercise discriminate between LQT1
and LQT2 genotypes. J Cardiovasc Electrophysiol. 2010;21:1242–1246.
27. Vincent GM, Jaiswal D, Timothy KW. Effects of exercise on heart rate,
QT, QTc and QT/QS2 in the Romano-Ward inherited long QT syndrome.
Am J Cardiol. 1991;68:498–503.
28. Walker BD, Krahn AD, Klein GJ, Skanes AC, Yee R. Burst bicycle exercise facilitates diagnosis of latent long QT syndrome. Am Heart J.
2005;150:1059–1063.
29. Vincent GM, Schwartz PJ, Denjoy I, Swan H, Bithell C, Spazzolini C,
Crotti L, Piippo K, Lupoglazoff JM, Villain E, Priori SG, Napolitano C,
Zhang L. High efficacy of beta-blockers in long-QT syndrome type 1:
contribution of noncompliance and QT-prolonging drugs to the occurrence
of beta-blocker treatment “failures”. Circulation. 2009;119:215–221.
30. Sumitomo N, Harada K, Nagashima M, Yasuda T, Nakamura Y, Aragaki
Y, Saito A, Kurosaki K, Jouo K, Koujiro M, Konishi S, Matsuoka S, Oono
T, Hayakawa S, Miura M, Ushinohama H, Shibata T, Niimura I. Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic
characteristics and optimal therapeutic strategies to prevent sudden death.
Heart. 2003;89:66–70.
31. Nam GB, Burashnikov A, Antzelevitch C. Cellular mechanisms underlying the development of catecholaminergic ventricular tachycardia. Circulation. 2005;111:2727–2733.
CLINICAL PERSPECTIVE
Downloaded from http://circep.ahajournals.org/ by guest on November 20, 2016
Epinephrine infusion has been reported to show excellent sensitivity and specificity for detection of long-QT syndrome and
catecholaminergic polymorphic ventricular tachycardia. We performed epinephrine infusion in 98 patients with unexplained
cardiac arrest (normal left ventricular function and QT interval) and 72 selected family members from the Cardiac Arrest
Survivors with Preserved Ejection Fraction Registry (CASPER) registry using the Mayo clinical escalating infusion protocol. Using the previously reported cutoff of an absolute QT interval prolongation by ≥30 ms at 0.10 μg/kg per minute, testing
was positive for long-QT syndrome in 31 patients (18%) and borderline in 24 (14%). Testing for catecholaminergic polymorphic ventricular tachycardia was positive in 7% and borderline in 5%. Correlation with exercise test results was moderate, but it raises concern about the specificity of the provoked changes. Targeted genetic testing of a proportion of abnormal
patients was positive in only 17% of long-QT syndrome patients and 13% of catecholaminergic polymorphic ventricular
tachycardia patients. Thus, epinephrine challenge provoked abnormalities in a substantial proportion of patients, although
exercise and genetic testing replicated the suggested diagnosis in a small proportion of patients. Despite concern regarding
the specificity of the observations in this at-risk population, epinephrine infusion combined with exercise testing and targeted
genetic testing is recommended in the workup of suspected familial sudden death syndromes.
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Epinephrine Infusion in the Evaluation of Unexplained Cardiac Arrest and Familial
Sudden Death: From the Cardiac Arrest Survivors With Preserved Ejection Fraction
Registry
Andrew D. Krahn, Jeffrey S. Healey, Vijay S. Chauhan, David H. Birnie, Jean Champagne,
Shubhayan Sanatani, Kamran Ahmad, Emily Ballantyne, Brenda Gerull, Raymond Yee, Allan
C. Skanes, Lorne J. Gula, Peter Leong-Sit, George J. Klein, Michael H. Gollob, Christopher S.
Simpson, Mario Talajic and Martin Gardner
Circ Arrhythm Electrophysiol. 2012;5:933-940; originally published online September 3, 2012;
doi: 10.1161/CIRCEP.112.973230
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Supplemental Material Figure 1. Proportion of patients with positive and borderline testing for LQTS (upper panel, left) and CPVT (upper panel, right). The lower panel summarizes the diagnostic yield of epinephrine testing, separated by clinical presentation. The left panel indicates the number of patients with positive testing for LQTS, and the right for CPVT. There was no difference in proportions between the familial sudden death groups (Familial SD) and the unexplained cardiac arrest group (UCA) for LQTS (chi squared p=0.49) or CPVT chi squared p=0.048). 100% abnormal borderline normal 80% 60% 40% 20% 0% LQTS CPVT