Impaired exercise capacity predicts sudden cardiac death in a low-risk population: enhanced specificity with heightened T-wave alternans.

Abstract

Because sudden cardiac death (SCD) is due to cardiac electrical instability, we postulated that prediction of this mode of death by exercise capacity will be enhanced by combined assessment with T-wave alternans (TWA), an index of repolarization abnormality.
The Finnish Cardiovascular Study enrolled consecutive patients (n=2,044) with a routine clinically indicated exercise test. Exercise capacity was measured in metabolic equivalents (METs) and TWA by time-domain modified moving average method.
During 47.2+/-12.8-month follow-up (mean+/-SD) 120 patients died; 58 were cardiovascular deaths, and 29 were SCD. In multivariate analysis after adjustment for sex, age, smoking, use of beta-blockers, as well as other common coronary risk factors, the relative risk of patients whose exercise capacity was depressed (MET < 8) was 8.8 (95% CI 2.0-38.9, P=0.004) for SCD. The combination of low exercise capacity (MET < 8) and elevated TWA (> or =65 microV) yielded relative risks for SCD of 36.1 (6.3-206.0, P<0.001), for cardiovascular mortality of 21.1 (6.7-66.2, P<0.001), and for all-cause mortality of 7.8 (3.5-17.4, P<0.001) over patients with neither factor.
Reduced exercise capacity, particularly in combination with heightened TWA, indicating enhanced cardiac electrical instability, powerfully predicts risk for SCD in patients referred for exercise testing.

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Impaired exercise capacity predicts sudden cardiac death in a low-riskImpaired exercise capacity predicts sudden cardiac death in a low-risk
population: enhanced specificity with heightened T-wave alternanspopulation: enhanced specificity with heightened T-wave alternans
Mikko Minkkinen a; Tuomo Nieminen bc; Richard L. Verrier d; Johanna Leino a; Terho Lehtimäki ae; Jari Viik f;
Rami Lehtinen agh; Kjell Nikus i; Tiit Kööbi ag; Väinö Turjanmaa ag; Mika Kähönen ag
a Medical School, University of Tampere, Tampere, Finland b Department of Pharmacological Sciences,
Medical School, University of Tampere, Tampere, Finland c Department of Internal Medicine, Päijät-Häme
Central Hospital, Lahti, Finland d Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,
MA, USA e Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Tampere University
Hospital, Tampere, Finland f Department of Biomedical Engineering, Tampere University of Technology,
Tampere, Finland g Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland h
Tampere Polytechnic—University of Applied Sciences, Tampere, Finland i Heart Centre, Department of
Cardiology, Tampere University Hospital, Tampere, Finland
First Published on: 19 March 2009
To cite this ArticleTo cite this Article Minkkinen, Mikko, Nieminen, Tuomo, Verrier, Richard L., Leino, Johanna, Lehtimäki, Terho, Viik, Jari, Lehtinen,
Rami, Nikus, Kjell, Kööbi, Tiit, Turjanmaa, Väinö and Kähönen, Mika(2009)'Impaired exercise capacity predicts sudden cardiac death
in a low-risk population: enhanced specificity with heightened T-wave alternans',Annals of Medicine,
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ORIGINAL ARTICLE
Impaired exercise capacity predicts sudden cardiac death in a low-risk
population: enhanced specificity with heightened T-wave alternans
MIKKO MINKKINEN1B.M.S., TUOMO NIEMINEN2M.D., PH.D, RICHARD L.
VERRIER3, PH.D, JOHANNA LEINO1B.M.S., TERHO LEHTIMA¨KI1,4M.D., PH.D,
JARI VIIK5, PH.D, RAMI LEHTINEN1,6,7, PH.D, KJELL NIKUS8M.D., TIIT KO¨O¨BI1,6
M.D., PH.D, VA¨INO¨ TURJANMAA1,6M.D., PH.D & MIKA KA¨HO¨NEN1,6M.D., PH.D
1Medical School, University of Tampere, Tampere, Finland,2Department of Pharmacological Sciences, Medical School,
University of Tampere, Tampere, Finland, and Department of Internal Medicine, Pa ¨ija ¨t-Ha ¨me Central Hospital, Lahti,
Finland,3Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA,4Laboratory of Atherosclerosis
Genetics, Department of Clinical Chemistry, Tampere University Hospital, Tampere, Finland,5Department of Biomedical
Engineering, Tampere University of Technology, Tampere, Finland,6Department of Clinical Physiology, Tampere University
Hospital, Tampere, Finland,7Tampere Polytechnic*University of Applied Sciences, Tampere, Finland, and8Heart Centre,
Department of Cardiology, Tampere University Hospital, Tampere, Finland
Abstract
Aims. Because sudden cardiac death (SCD) is due to cardiac electrical instability, we postulated that prediction of this mode
of death by exercise capacity will be enhanced by combined assessment with T-wave alternans (TWA), an index of
repolarization abnormality.
Material and methods. The Finnish Cardiovascular Study enrolled consecutive patients (n?2,044) with a routine clinically
indicated exercise test. Exercise capacity was measured in metabolic equivalents (METs) and TWA by time-domain
modified moving average method.
Results. During 47.2912.8-month follow-up (mean9SD) 120 patients died; 58 were cardiovascular deaths, and 29 were
SCD. In multivariate analysis after adjustment for sex, age, smoking, use of b-blockers, as well as other common coronary
risk factors, the relative risk of patients whose exercise capacity was depressed (METB8) was 8.8 (95% CI 2.0?38.9,
P?0.004) for SCD. The combination of low exercise capacity (METB8) and elevated TWA (]65 mV) yielded relative
risks for SCD of 36.1 (6.3?206.0, PB0.001), for cardiovascular mortality of 21.1 (6.7?66.2, PB0.001), and for all-cause
mortality of 7.8 (3.5?17.4, PB0.001) over patients with neither factor.
Conclusions. Reduced exercise capacity, particularly in combination with heightened TWA, indicating enhanced cardiac
electrical instability, powerfully predicts risk for SCD in patients referred for exercise testing.
Key words: Arrhythmia, electrocardiography, exercise, mortality, tachyarrhythmia
Introduction
Exercise capacity predicts all-cause and cardiac
mortality in men more powerfully than do other
cardiac risk factors (1). This prognostic utility is
similar among women (2,3) and across racial groups
(4). Surprisingly, its potential to estimate risk speci-
fically for sudden cardiac death (SCD) has not been
investigated. This is an important gap in our knowl-
edge, as reduced exercise capacity could reflect the
extent of heart disease, including myocardial scarring
and poor myocardial perfusion that create a hetero-
geneous myocardial substrate with increased suscept-
ibility to lethal re-entrant arrhythmias. Combined
testing with T-wave alternans (TWA), a marker of
cardiac electrical instability, during routine symp-
Correspondence: Mika Ka ¨ho ¨nen, MD, PhD, Department of Clinical Physiology, Tampere University Hospital, FI-33520, Tampere, Finland. Fax: ?358 3
311 65511. E-mail: mika.kahonen@uta.fi
(Received 14 July 2008; revised 6 January 2009; accepted 12 January 2009)
Annals of Medicine.
2009, 1?10, iFirst article
ISSN 0785-3890 print/ISSN 1365-2060 online # 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)
DOI: 10.1080/07853890902802971
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tom-limited exercise tests could demonstrate an
association with SCD as well as increase the strength
of prediction.
The literature provides clues supporting the
rationale for combined analysis of exercise capacity
with TWA. Tapanainen and co-workers (5) demon-
strated in postmyocardial infarction patients that
inability to achieve a target heart rate of 105?110
beats/min, as required for spectral TWA testing, was
itself predictive of cardiovascular mortality. More
recently, it has been advised that spectral TWA tests
previously considered ‘indeterminate’ based on not
achieving a target heart rate should be classified as
‘abnormal’ or ‘non-negative’ (6). However, target
heart rate is not a reliable measure of exercise
capacity, as patients’ inability to increase heart rate
may be influenced by many factors including sinus
node responsiveness or medications, particularly
beta-adrenergic blocking agents (b-blockers), as
well as by mechanical function of the heart. Meta-
bolic equivalents (METs) have been shown to be a
more reliable measure of exercise capacity (7).
Based on extensive evidence that SCD is due to
cardiac electrical instability, we postulated that
prediction of this mode of death by exercise capacity
will be enhanced by combined assessment with
TWA, an index of repolarization abnormality. We
applied the time-domain modified moving average
method for TWA analysis (8), which, because of its
intrinsic flexibility, permits TWA analysis during
routine symptom-limited exercise protocols in which
exercise capacity can be measured. The method has
undergone extensive validation and performs at a
resolution of 1 microvolt, equivalently to the spectral
method (9,10). We tested its utility to improve SCD
risk stratification in a general population of patients
referred for a clinical exercise test.
Material and methods
Study cohort
All consecutive patients coming for an exercise
test at Tampere University Hospital and willing to
participate were enrolled in the Finnish Cardiovas-
cular Study (FINCAVAS). Between October 2001
and the end of 2004, a study population of 2,212
patients (1,400 men and 812 women) was recruited.
Results of analysis of TWA alone in about half of the
patients (1,037) have been reported (11). A total of
2,044 patients (1,305 men and 739 women) had
technically successful exercise tests (92.4% of all
tests) and were studied in the current investigation
(Table I). A test was technically adequate if storing
hemodynamic data and continuous digital electro-
cardiogram as well as TWA assessment and exercise
capacity recording in METs were successful.
The main indications for exercise testing were
suspicion of coronary heart disease (46%), palpita-
tion or sense of arrhythmia (21%), evaluation of
work capacity (18%) and adequacy of coronary
heart disease treatment (16%), as well as obtaining
an exercise test profile prior to an invasive operation
(14%) or after myocardial infarction (8%); some
patients had more than one indication. The Ethics
Committee of Tampere University Hospital District
of Pirkanmaa, Finland, approved the study protocol,
and all patients gave informed consent prior to the
interview and measurements, as stipulated in the
Declaration of Helsinki.
Study flow
After an informed consent was signed, the med-
ical history of each patient was collected with a
computer-based questionnaire form. Thereafter, the
exercise test was performed.
Exercise test protocol
Prior to the exercise stress test, subjects lay down in
the supine position for 10 minutes, and the resting
electrocardiogram was digitally recorded. Exercise
testing was performed using a bicycle ergometer with
electrical brakes. The lead system used was the
Mason-Likar modification of the standard 12-lead
Key messages
.
Reduced exercise capacity powerfully pre-
dicts risk for sudden cardiac death in a
general population of patients referred for a
clinical exercise test.
T-wave alternans, an indicator of ventricu-
lar electrical instability, adds significantly to
the prognostic strength of reduced exercise
capacity.
.
Abbreviations
b-blockers
CI
FINCAVAS Finnish Cardiovascular Study
METmetabolic equivalent
mV microvolt
NPV negative predictive value
PPVpositive predictive value
SCDsudden cardiac death
TWA T-wave alternans
Wwatt
beta-adrenergic blocking agents
confidence interval
2
M. Minkkinen et al.
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system (12). The initial work-load varied from
20 watts (W) to 30 W, and the load was increased
stepwise by 10?30 W every minute. Continuous
electrocardiograms were digitally recorded at 500
hertz with CardioSoft exercise system (Version 4.14,
GE Healthcare, Freiburg, Germany).
Heart rate was continuously registered with
electrocardiograms during the tests, while systolic
and diastolic arterial pressures were measured with a
brachial cuff every 2 minutes. Exercise capacity in
METs was estimated on the standardized basis of
maximum work-load and weight of the patient, with
1 MET equivalent to 3.5 mL oxygen uptake/kilo-
gram/min.
Measurement of TWA
TWA was analyzed fully automatically by investiga-
tors blinded to clinical outcomes with the released
version of GE Healthcare Modified Moving Average
software. Modified moving average analysis (8)
calculates and compares separate average morphol-
ogies of odd and even beats. Continuous updating
for every incoming beat by a weighting factor of 1/8
of the difference between the on-going average and
the new incoming beat produces continuous moving
averages of odd and even beats. This approach is
intrinsically robust and is suitable for TWA analysis
during periods of activity or fluctuating heart rates
(13). Algorithms have also been incorporated to
decrease the influence of noise and artifacts, such as
those caused by pedaling and respiration (14). The
following steps were taken to ensure quality control
of TWA values. Throughout the analysis, beat-
labeling was performed to exclude the suspect and
preceding beat based on noise and prematurity
according to several criteria. These included: beats
with?20 microvolts of noise, which was measured
during the isoelectric segments; regions with ?25%
of noisy beats; and ventricular premature beats.
Standard precordial leads (V1 to V6) were
recorded continuously during the entire exercise
test. The highest TWA value in any lead during the
exercise-phase at heart ratesB125 beats/min was
derived. This heart rate limit was set, as inaccuracies
in TWA measurement can result at heart rates
exceeding this range (15). TWA results in limb leads
were excluded as these leads are subject to significant
motion artifact, as confirmed by visual inspection of
templates of superimposed electrocardiograms in the
GE Healthcare system. Precordial leads have also
been shown to be optimum for TWA measurement
(16,17).
The TWA values obtained by the modified
moving average method are 4- to 6-fold higher
than the values reported by the spectral method.
This difference is due primarily to the fact that
the time-domain modified moving average method
Table I. Patient characteristics and unadjusted percentage of beta-adrenergic blocking agent (b-blocker) users as well as prevalence of
cardiovascular diseases, symptoms, and risk factors for all participants (n?2,044) divided by gender and separately for men with sudden
cardiac death (SCD) (n?28). The differences between men with and without SCD were tested by using t test for independent samples for
continuous variables and chi-square test for categorical variables.
MenWomenMen with SCD
(n?1305)(n?739)(n?28)
MeanSDMeanSDMean SD
P
Age (years)
BMI (kg/m2)
Weight (kg)
Height (cm)
Heart rate at supine rest (bpm)
SAP at supine rest (mmHg)
Reached heart rate of expected maximum (%)
57
27.5
85
176
62
135
78
13
4.2
14
7
11
18
14
57
27.4
72
162
65
138
80
1361
27.1
83
175
60
132
69
13
4.3
16
8
9
28
13
0.069
0.593
0.457
0.516
0.177
0.552
0.001
5.0
13
6
11
20
14
%
63
32
44
25
53
40
13
%
51
15
29
14
45
40
12
%
89
25
75
54
64
29
21
b-blockers
Smoking
CHD
Prior MI
Hypercholesterolemia
Hypertension
Diabetes
0.003
0.540
0.002
0.001
0.254
0.246
0.154
SCD?sudden cardiac death; BMI?body mass index; SAP?systolic arterial pressure; b-blockers?beta-adrenergic blocking agents;
CHD?coronary heart disease; MI?myocardial infarction.
Exercise capacity, T-wave alternans, and mortality
3
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Page 5

calculates the maximum difference in amplitudes
of successive T-waves, while the spectral method
computes an average value from its spectra, which
are determined across the entire T-wave and across
128 beats.
Ejection fraction
Measurement of left ventricular ejection fraction is
not routine for patients referred for a clinical exercise
test. However, ejection fraction was determined
for 1,117 (55%) of study patients with echocardio-
graphy or isotope techniques within 6 months of
exercise testing.
Follow-up
Death certificates listing causes of death using the
tenth revision of the International Classification of
Diseases (ICD-10) were received from the Causes of
Death Register, maintained by Statistics Finland, in
April 2007; this source has been shown to be reliable
(18). Diagnosis numbers and certificate texts were
used to classify deaths as all-cause, cardiovascular, or
SCD, i.e., cardiovascular death within 24 hours after
onset of symptoms. Autopsy rate was 40% for all
deaths and 60% for patients with SCD.
Statistical analysis
Predictivity for SCD and for cardiovascular and all-
cause mortality by METs with and without elevated
TWA was analyzed using Cox proportional hazards
models. Analyses of exercise capacity in METs were
performed with the cut-point of B8, which has been
used in studies in women (19,20) but to our knowl-
edge not in studies with men. In subgroup analyses
in women, the cut-point of B5 (2) was also used.
The Pearson correlations between maximum heart
rate and exercise capacity in METs and between
TWA magnitude and maximum heart rate were
calculated.
For analyses of TWA, the cut-point of 65 micro-
volts (mV) in precordial leads was used, because it
had the best prognostic power in our previous study
(11). Low exercise capacity and TWA were com-
bined in one categorical variable with three different
groups of patients: MET]8 and TWAB65 mV;
METB8 or TWA]65 mV; and METB8 and
TWA]65 mV. Thereafter, risk for all-cause and
cardiovascular death as well as for SCD was esti-
mated with Cox regression analysis using the follow-
ing covariates (21): sex, age, body mass index, daily
smoking (yes/no), use of b-blockers (yes/no), as well
as prior diagnoses of coronary heart disease (yes/no),
myocardial infarction (yes/no), and diabetes (yes/no)
(Table II). Use of b-blockers was defined as ‘no’ if
the patient did not use b-blockers or if the pause
in b-blocker use before the test was 3 days or
more. Sensitivity and specificity as well as positive
and negative predictive values were calculated for
exercise capacity alone and in combination with
TWA compared to patients with neither factor
(Table III).
Statistical analyses were performed with the SPSS
release 15.0 for Windows (SPSS Inc., Chicago,
Illinois). All statistical tests were two-tailed and
used an alpha level of 0.05.
Results
Among the 2,044 enrolled patients, 120 deaths
(5.9%) occurred over the succeeding 47.2912.8
months (mean9SD). Of those, 58 (2.8%) were
categorized as cardiovascular deaths and 29 (1.4%)
further as SCD. Thus, the cardiovascular mortality
of the present patients was 0.71%/year. Prevalence
of all-cause death, cardiovascular death, and SCD in
women was 3.8% (n?28), 1.1% (n?8), and 0.1%
(n?1), respectively; in men, the prevalence was
7.0% (n?92), 3.8% (n?50), and 2.1% (n?28),
respectively. Left ventricular ejection fraction, re-
ported for 1,117 patients, was 66914% (mean9
SD). Of these, 103 patients (9.2%) presented with
ejection fraction B50%, 39 patients (1.9%) with
ejection fraction B40%, and 10 patients (0.9%)
with ejection fraction B30%. Among the 29 SCD
cases, ejection fraction was reported for 15 (52%)
and was 60.5915.7 (mean9SD). Only 24 patients
(1.2%) had an implantable cardioverter defibrillator.
Male patients with SCD reached lower percent of
expected heart rate, more frequently had coronary
heart disease and prior myocardial infarction, and
were more often on b-blocker treatment than
those who did not experience SCD in the follow-
up (Table I). The mean value (9SD) for peak TWA
levels measured during exercise in precordial leads
was 30921 mV. The Pearson correlation was 0.537
(PB0.001) between maximum heart rate and ex-
ercise capacity in METs and ?0.099 (PB0.001)
between maximum heart rate and TWA magnitude.
Exercise capacity and mortality
In our population of consecutive patients referred for
clinical exercise testing, 58.5% had reduced exercise
capacity. The mean value (9SD) for exercise
capacity in METs for men (1,305) was 7.493.0
and for women (739) was 6.792.8. For patients
with reduced exercise capacity (METB8, n?
4
M. Minkkinen et al.
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1,195), the unadjusted prevalence of all-cause death
was 8.6%, cardiovascular death 4.4%, and SCD
2.3%. For those with preserved exercise capacity
(MET]8, n?849), the prevalence was 2.0%,
0.6%, and 0.2%, respectively.
The adjusted relative risk for SCD for those with
poor exercise capacity (METB8) was 8.8 (95%
confidence interval (CI) 2.0?38.9, P?0.004), was
5.2 (2.0?13.6, P?0.001) for cardiovascular mortal-
ity, and was 3.3 (1.9?5.6, PB0.001) for all-cause
mortality. Age, sex, body mass index, use of b-
blockers, and prior diagnosis of myocardial infarc-
tion and coronary heart disease were significant
covariates for death from any cause. Age, sex, body
mass index, and use of b-blockers were significant
covariates for cardiovascular mortality, while only
sex was a significant covariate for SCD. MET was a
highly sensitive predictor (93.1%) of SCD, with high
negative predictive value (NPV) (99.8%) (Table III).
Similar predictivity was determined for cardiovascu-
lar and total mortality (Table III).
As a continuous variable, increasing MET sig-
nificantly improved survival in terms of all-cause and
cardiovascular mortality and SCD (relative risk
0.77 per 1 MET increase, 95% CI 0.70?0.84, PB
0.001 for all-cause mortality; relative risk 0.69 per 1
MET increase, 95% CI 0.60?0.80, PB0.001 for
cardiovascular mortality; and relative risk 0.67 per 1
MET increase, 95% CI 0.57?0.83, PB0.001 for
SCD).
In the subgroup analyses in women (n?739)
increasing MET as a continuous variable signifi-
cantly improved the survival in terms of all-cause
and cardiovascular mortality (relative risk 0.77 per
1 MET increase, 95% CI 0.62?0.95, P?0.016 for
all-cause mortality; and relative risk 0.52 per 1 MET
increase, 95% CI 0.32?0.83, P?0.006 for cardio-
vascular mortality). The cut-point of METB8 did
not reach significance in women, but the cut-point of
METB5 predicted statistically significantly cardio-
vascular mortality (relative risk 15.0, 95% CI 2.0?
111.8, P?0.008) in women.
In men the results were highly comparable to
results of the all participants.
Exercise capacity, TWA, and mortality
The predictive power of TWA (]65 mV) alone with
covariates used in this study remained highly sig-
nificant in this expanded database, resulting in a
relative risk of 2.2 (1.1?4.2, P?0.018) for total
mortality, 4.0 (1.9?8.5, PB0.001) for cardiovascular
mortality, and 3.9 (1.4?11.5, P?0.011) for SCD.
SCD risk was further categorized according
to TWA test results. Three groups of patients,
Table II. Adjusted relative risks for all-cause mortality, cardiovascular mortality, and sudden cardiac death according to exercise capacity in metabolic equivalents (MET) and T-wave alternans
(TWA), adjusted by covariates used in the Cox regression models (n?2,044).
All-cause mortality
Cardiovascular mortality
Sudden cardiac death
95% CI
95% CI
95% CI
RR
Lower
Upper
P
RR
Lower
Upper
P
RR
Lower
Upper
P
METB8 and TWA]65*
7.8
3.5
17.4
B0.001
21.1
6.7
66.2
B0.001
36.1
6.3
206.0
B0.001
METB8 or TWA]65*
2.8
1.6
4.8
B0.001
4.1
1.6
10.8
0.004
7.0
1.6
31.1
0.011
Age (y)
1.0
1.0
1.1
B0.001
1.0
1.0
1.1
0.014
1.0
1.0
1.0
0.773
Sex (f/m)
1.9
1.2
3.0
0.004
3.3
1.6
7.2
0.002
14.8
2.0
110.8
0.009
BMI (kg/m2)
0.9
0.9
1.0
B0.001
0.9
0.9
1.0
0.008
0.9
0.8
1.0
0.072
Smoking (no/yes)
1.3
0.9
2.0
0.180
0.9
0.5
1.6
0.650
0.6
0.2
1.4
0.249
Prior MI (no/yes)
1.8
1.0
3.1
0.036
2.1
1.0
4.1
0.044
1.9
0.7
4.9
0.193
Diabetes (no/yes)
1.3
0.8
2.1
0.297
1.7
0.9
3.2
0.107
1.7
0.7
4.2
0.282
b-blockers (no/yes)
1.8
1.1
2.9
0.014
2.9
1.3
6.5
0.012
3.4
1.0
11.8
0.055
CHD (no/yes)
0.5
0.3
0.9
0.026
0.9
0.4
1.9
0.702
1.2
0.4
3.5
0.761
RR?relative risk; CI?confidence interval; mV?microvolt; BMI?body mass index; MI?myocardial infarction; b-blockers?beta-adrenergic blocking agents; CHD?coronary heart disease.
*Compared to patients with neither factor
Exercise capacity, T-wave alternans, and mortality
5
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MET]8 and TWAB65 mV, METB8 or TWA]
65 mV, and METB8 and TWA]65 mV, contained
811, 1177, and 56 patients, respectively. The
combination of poor exercise capacity and elevated
TWA identified patients with the highest prevalence
of SCD and of cardiovascular and total mortality
(Figure 1). Survival curves depict events across 4
years of follow-up for the combined analysis of
reduced METB8 and elevated TWA (]65 mV)
(Figure 2). The adjusted relative risk for SCD
for patients with both reduced exercise capa-
city (METB8) and heightened TWA (]65 mV)
was 36.1 (6.3?206.0, PB0.001), for cardiovascular
mortality was 21.1 (6.7?66.2, PB0.001), and for all-
cause mortality was 7.8 (3.5?17.4, PB0.001), over
patients with neither factor (Table II). For SCD,
the only significant covariate was sex. Combined
analysis of SCD risk with METs and TWA]65 mV
yielded high specificity (94.0%) while retaining high
NPV (99.8%) (Table III). A representative example
of exercise-induced TWA is provided (Figure 3).
The combinationof
(METB8) and elevated TWA (]65 mV) did not
reach significance in women. In men the results were
highly comparable to the results of all participants.
low exercise capacity
Discussion
Our study is the first to demonstrate that reduced
exercise capacity is a risk factor for SCD. It also
provides evidence that TWA, an indicator of ven-
tricular electrical instability, adds significantly to the
prognostic strength of reduced exercise capacity.
This full-cohort examination of risk stratification
with TWA enrolled more than 2,000 patients. In half
of the patients, left ventricular ejection fraction was
measured, and in 90% of these, it was found to be
normal. It is probable although not documented that
the remaining half of the cohort, in whom ejection
fraction was not measured, had even better cardio-
vascular health, because ejection fraction determina-
tion was not indicated. Thus, the present results are
relevant to a large group of individuals whose
elevated risk for SCD and major cardiovascular
events is not disclosed by other contemporary tests.
Previous studies
Exercise capacity is a superior predictor of all-cause
and cardiovascular mortality (1?4). The usefulness
of exercise-induced TWA in predicting arrhythmic
events and death has been investigated (11,22?25).
We reported in ?1,000 FINCAVAS patients that
TWA assessed during routine symptom-limited
exercise testing is a strong risk marker for SCD
and cardiovascular and total mortality in a general
population of patients referred for a clinical exercise
test (11). By contrast, most studies of TWA have
been performed in populations with high risk of life-
threatening arrhythmias (22,23,25) or lower-risk
patients with prior myocardial infarction (24) and
employed spectral analysis of TWA during a target
heart rate exercise protocol. These TWA test results
are indeterminate in 20%?40% of cases (6) due to
patient factors, in the majority to inability to achieve
the target heart rate of 105?110 beats/min. Classi-
fication of these indeterminate tests as ‘abnormal’
conferred prediction to avoid repetition of capacity
although exercise capacity itself was not measured.
Thus, the present study, in which exercise capacity
was measured, is the first to provide direct evidence
of its predictive value for SCD, particularly when
combined with TWA.
Current investigation
Our study provides new evidence that in a general
population of patients referred for a clinical exercise
test, reduced exercise capacity increases risk for
SCD as well as for cardiovascular death and total
mortality. When heightened TWA, a validated mar-
ker of arrhythmia risk, is also present, risk of SCD is
further elevated over that of patients with neither
factor (Table II). Poor exercise capacity alone was
found to be a highly sensitive (93.1%) marker of
SCD risk, with specificity of 42.0%, as it detected 27
of 29 cases of SCD (Table III). Combined analysis
with elevated TWA greatly improved the specificity
of the test, to 94.0%.
Table III. Sensitivity (Sn), specificity (Sp), as well as positive
(PPV) and negative (NPV) predictive values for sudden cardiac
death and for cardiovascular and all-cause mortality (n?2,044).
Sn SpPPV NPV
METB8:*
Sudden cardiac death
Cardiovascular death
All-cause death
93.1
91.4
85.8
42.0
42.5
43.2
2.3
4.4
8.6
99.8
99.4
98.0
METB8 and TWA]65 mV:*
Sudden cardiac death
Cardiovascular death
All-cause death
66.7
61.5
37.0
94.0
94.4
94.5
7.1
14.3
17.9
99.8
99.4
97.9
MET?metabolic equivalents; TWA?T-wave alternans
+Compared to patients with neither factor
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The NPV for SCD for patients with both low
exercise capacity and high exercise-induced TWA
was99.8%overpatients
(Table III). This finding is similar to our previous
results using only exercise-induced TWA as predic-
tor (98.6%) (11) and to results of TWA testing with
the spectral method, for which NPV averages 97.2%
(95% CI 96.5?97.9) (22). Reduced exercise capacity
alone does not provide high positive predictive value
(PPV) (2.3%) for SCD in our low-risk population
(Table III). However, when low exercise capacity is
combined with TWA]65 mV, PPV for SCD rose to
7.1% (Table III), which is highly comparable to the
8.0% result achieved with only TWA as a predictor
in our previous study (11) and to the 6.0% level
(95% CI 4.5?7.4) provided by TWA testing with the
spectral method for cardiac arrhythmic events in
low-risk patients (22).
With the exception of sex differences, the relative
risks linked to traditional cardiovascular risk markers
(Table II) were lower than those for reduced exercise
capacity, with or without TWA. Thus, the combina-
tion of depressed exercise capacity and heightened
TWA provides a marked prognostic index indepen-
dent of traditional risk factors.
In the subgroup analyses in women, low exercise
capacity (METB5) predicted cardiovascular mor-
with neither factor
tality, and increasing MET as continuous variable
improved survival for all-cause and cardiovascular
mortality.However,the
(METB8) alone or in combination with elevated
TWA (]65 mV) did not reach significance as
predictor of all-cause or cardiovascular mortality in
women. This may be due to the smaller number of
events in this subgroup. Thus, further studies are
needed to evaluate the prognostic power of com-
bined analysis of low exercise capacity and elevated
TWA in women.
SCD in a general population without congestive
heart failure most commonly results from ventricular
fibrillation triggered by an ischemic event (26).
TWA reflects the presence of abnormal repolariza-
tion and electrophysiologic inhomogeneities that
underlie vulnerability to ventricular fibrillation dur-
ing myocardial ischemia (27). Exercise testing serves
to expose latent electrical instability, as indicated by
elevated levels of TWA. When analyzed together,
exercise capacity and TWA provide supplementary
information that strengthens the predictive value of
either parameter alone, to 36-fold over risk in the
absence of both factors (Table II). The fact that the
end-points measure largely different characteristics
is likely to underlie the additive effect. Exercise
capacity essentially provides a measure of cardiac
low exercisecapacity
Figure 1. Prevalence of all-cause and cardiovascular mortality as well as sudden cardiac death (SCD) among patients according to
metabolic equivalents (MET) and T-wave alternans (TWA). The P-values are from chi-square test. The subjects with metabolic equivalents
(MET)]8 and T-wave alternans (TWA)B65 microvolts (mV) were compared to the subjects with either METB8 or TWA]65 mVand to
the subjects with METB8 and TWA]65 mV.
Exercise capacity, T-wave alternans, and mortality
7
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Page 9

mechanical function, whereas TWA is an indicator
of cardiac electrical instability.
There are some limitations in our study. Estab-
lishing definitively that an event is SCD is inherently
challenging. Our main criterion was death within
24 hours following onset of symptoms. The majority
of deaths that were classified as SCD in this study
were caused by acute coronary events, which have
been shown to be the triggers for ventricular
tachyarrhythmias leading to SCD (26,28,29). There
were no signs of pulmonary embolism or pulmonary
edema in autopsy information in patients with SCD.
The presence of elevated exercise-induced TWA in
patients with reduced exercise capacity was a stron-
ger predictor of SCD than of either cardiovascular
mortality or total deaths (Table II). The combina-
tion of heightened TWA with reduced exercise
capacity also improved prediction of all-cause mor-
tality, which is a definite end-point. A second
limitation is the low PPV for SCD of exercise
capacity alone, which is typical of low-risk groups,
and which is improved by combined assessment with
TWA. A third limitation is that we do not have
information on changes in parameters affecting
mortality risk (e.g. smoking, life-style, and medica-
tions) during follow-up. As with any observational
study, it is not possible to draw causal inferences,
and differences in variables that were not adjusted
for or residual confounding may exist. Although the
data reported in our study are from bicycle erg-
ometer tests, it is likely that the results can be also
generalized to populations undergoing a clinically
indicated treadmill exercise test.
A broad implication of the present finding is that
a mainstay measurement, namely exercise capacity,
especially when combined with TWA assessment, is
capable of identifying individuals whose risk for
SCD is elevated but whose ejection fraction is
normal. As exercise capacity was reduced in 58.5%
of our population of consecutive patients referred for
clinical exercise testing, TWA measurement can
provide useful confirmatory information regarding
their cardiac status. Because both parameters can be
acquired automatically during the course of routine,
symptom-limited exercise testing, without a specia-
lized protocol or non-standard electrodes, this test
has the potential for screening broad, diverse popu-
lations. The population tested was at relatively low
risk of events, the group in which the greatest
incidence of SCD occurs but in which identification
of SCD risk has been elusive (26). Because com-
bined measurement of mechanical function by
exercise capacity and of cardiac electrical instability
by TWA provides important insights into a potential
basis for patients’ risk for arrhythmia, it could prove
helpful in identifying therapeutic targets for SCD
reduction.
Acknowledgements
Financial support was received from the Medical
Research Fund of Tampere University Hospital, the
Finnish Cultural Foundation, the Finnish Founda-
tion for Cardiovascular Research, the Academy of
Finland (grant no. 104821), the Emil Aaltonen
Foundation, Finland, and the Tampere Tuberculosis
Foundation. The authors thank the staff of the
Department of Clinical Physiology for collecting
the exercise test data. Automated analysis of TWA
was performed by Willi Kaiser of GE Healthcare,
Freiburg, Germany, who was blinded to patient
characteristics and clinical outcomes.
Figure 2. Adjusted survival curves by Cox regression anlysis for
subjects with metabolic equivalents (MET)]8 and T-wave
alternans (TWA)B65 microvolts (mV) (the upper curve in each
panel), METB8 or TWA]65 mV (the middle curve), and
METB8 and TWA]65 mV (the lower curve) for a) all-cause
mortality, b) cardiovascular mortality, and c) sudden cardiac
death. Please note that the scale for the y-axis is from 0.75 to 1.00.
8
M. Minkkinen et al.
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Declaration of interest: Dr Richard L. Verrier is
co-inventor of patents for T-wave alternans measure-
ment, including by the modified moving average
method, which were assigned to Georgetown Uni-
versity and Beth Israel Deaconess Medical Center
and licensed to GE Healthcare. The other authors
do not have any conflicts of interest. The authors
alone are responsible for the content and writing of
the paper.
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