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Cardiac Arrhythmias and Stroke
Increased Risk in Men With High Frequency of Atrial Ectopic Beats
Gunnar Engström, MD, PhD; Bo Hedblad, MD, PhD; Steen Juul-Möller, MD, PhD;
Patrik Tydén, MD; Lars Janzon, MD, PhD
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Background and Purpose—With the exception of atrial fibrillation (AF), little scientific attention has been given the
associations between cardiac arrhythmias and incidence of stroke. We sought to study whether atrial and ventricular
arrhythmias assessed during a 24-hour ambulatory ECG registration are associated with incidence of stroke.
Methods—The population-based cohort “Men Born in 1914” was examined with 24-hour ambulatory ECG registrations
at 68 years of age. Four hundred two men without previous myocardial infarction or stroke were included, and 236 of
them had hypertension (ⱖ160/95 mm Hg or treatment). Fourteen-year rates of stroke (fatal and nonfatal) and all-cause
mortality were updated from national and regional registers. Frequent or complex ventricular arrhythmias was defined
as Lown class 2 to 5. A high frequency of atrial ectopic beats (AEB) was defined as the fifth quintile (ie, ⱖ218 AEB
per 24 hours).
Results—Fifty-eight men suffered a first stroke during the follow-up. Stroke rates (per 1000 person-years) among men with
AF (n⫽14), with frequent AEB (n⫽77), and without AF or frequent AEB (n⫽311) were 34.5, 19.5, and 11.6,
respectively. The corresponding values among men with hypertension were 40.7, 32.3, and 14.7, respectively. Frequent
AEB (compared with absence of AF and frequent AEB) was significantly associated with stroke among all men (relative
risk⫽1.9; 95% CI, 1.02 to 3.4; P⫽0.04) and among hypertensive men (relative risk⫽2.5; 95% CI, 1.3 to 4.8; P⫽0.009)
after adjustments for potential confounders. The increased stroke rates among men with Lown class 2 to 5 did not reach
statistical significance.
Conclusions—A high frequency of AEB is associated with an increased incidence of stroke. (Stroke. 2000;31:2925-2929.)
Key Words: arrhythmia 䡲 cerebrovascular disorders 䡲 electrocardiography
T
he association between atrial fibrillation (AF) and stroke
is well documented.1– 6 Prevalence of AF has been
estimated to be 2% to 4% among elderly individuals,1–3,7 and
10% of the stroke morbidity among persons aged 70 years has
been attributed to this condition.1 Frequent or complex
ventricular arrhythmias have been reported in a sizeable
proportion, approximately one third, of healthy elderly individuals.7–10 However, with the exception of AF, the associations between incidence of stroke and cardiac arrhythmias
have received little scientific attention.
“Men Born in 1914,” from Malmö, Sweden, is a
population-based prospective study of cardiovascular diseases and its major determinants. Previous studies from the
cohort have shown that ventricular arrhythmias are associated
with increased mortality and cardiac event rates.7,8,11 The
objective of the present follow-up was to study whether
incidence of stroke is associated with the occurrence of
ventricular arrhythmias and atrial ectopic beats (AEB) assessed during 24-hour ambulatory ECG registrations.
Subjects and Methods
Six hundred twenty-one men, representing a random 50% sample of
all 68-year-old men living in Malmö, Sweden, were invited to
participate in a prospective study on cardiovascular diseases when
they were close to their 68th birthday. Five hundred men (80.5%)
participated. The baseline examination included an examination of
cardiovascular history and status. Four hundred fifty-six (91%) took
part in the 24-hour ambulatory ECG registration. After the exclusion
of men with history of myocardial infarction and stroke (according to
questionnaire and hospital records), 402 men remained. The project
was approved by the Lund University Ethics Committee. The
characteristics of the nonparticipating group have been reported in a
previous article.12
Assessments of Health Status
Blood pressure was measured in the morning with the subjects in a
sitting position. Pressure was measured to the nearest 5 mm Hg with
a mercury sphygmomanometer and a 12⫻26-cm rubber cuff. Men
with systolic blood pressure ⱖ160 mm Hg or diastolic blood
pressure ⱖ95 mm Hg and men with medical treatment for hypertension were classified as hypertensive.13
History of angina pectoris was assessed by means of the Rose
questionnaire.14
Received May 25, 2000; final revision received September 6, 2000; accepted September 6, 2000.
From the Departments of Community Medicine (G.E., B.H., P.T., L.J.) and Cardiology (S.J-M. P.T.), Malmö University Hospital (Sweden).
Correspondence to Gunnar Engström, MD, PhD, Department of Community Medicine, Malmö University Hospital, S-20502 Malmö, Sweden. E-mail
[email protected]
© 2000 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
2925
2926
Stroke
December 2000
TABLE 1.
Mortality and Stroke During 14 Years Among All Men in Relation to Findings From 24-Hour Ambulatory ECG Recordings
All-Cause Mortality
Not AF or frequent AEB
Stroke
n
Deaths,
n (%)
Total
Follow-Up, y
Deaths/
1000 PY
P
Events, n (%)
Follow-Up, y
Events/
1000 PY
P
Reference
311
130 (42)
3504
37.1
Reference
39 (13)
3364
11.6
Frequent AEB, not AF
77
40 (52)
828
48.3
0.23
15 (19)
768
19.5
0.07
AF
14
11 (79)
126
87.3
0.002
4 (29)
116
34.5
0.007
Lown class 0–1
259
107 (41)
2958
36.2
Reference
36 (14)
2817
12.8
Reference
Lown class 2–5
143
74 (52)
1500
49.3
0.02
22 (15)
1431
15.4
0.81
All men
402
181 (45)
4458
40.6
58 (14)
4248
13.7
PY indicates person-years.
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Smoking was assessed by means of a structured interview. Men
who never smoked or who had stopped smoking at least 1 month
before the examination were categorized as nonsmokers.
Total plasma cholesterol was analyzed at the laboratory of the
Malmö University Hospital with standard methods. Blood samples
for determination of lipids and glucose were drawn after a minimum
fasting period of 8 hours. Diabetes mellitus was defined as fasting
blood glucose ⱖ7.0 mmol/L or medication for diabetes mellitus. All
cases were validated by review of hospital records.
Ambulatory 24-Hour ECG Recordings
The procedures of the 24-hour ECG recordings and analyses of
arrhythmias were described previously.7,11 An ECG tape recorder
(Oxford Medilog II, FM type) with 2 bipolar electrodes in the V2 and
V6 positions was used. An interactive computer (Oxford Medilog
MA 14/20) was used for interpretation of type of ventricular
arrhythmia. In addition, all tapes were analyzed by a well-trained
technician.
Ventricular arrhythmia was categorized with regard to number and
type according to Lown and Wolf15: class 0, no ventricular ectopic
beats; class 1, ⬍720 per 24 hours; class 2, ⱖ720 per 24 hours; class
3, multiform, bigeminal, or trigeminal; class 4a, couplets; class 4b,
ventricular tachycardia; and class 5, R-on-T type. Frequent or
complex ventricular arrhythmias were defined as Lown class 2 to
5.8,11
The following criteria were used for detection of AEB: a reduced
RR interval of ⱖ25%, presence of a P wave, and a QRS width ⬍0.12
seconds. Categorization of AEB is based on distribution of the
present sample. High frequency was defined as the fifth quintile (ie,
ⱖ218 AEB per 24 hours). Absence of P waves and irregular
ventricular activity or irregular ventricular activity in presence of F
waves was used as a criterion of AF. Men with single episodes or
intermittent AF were classified as having AF.
Mortality Rates
All probands were followed from the baseline examination until their
death or December 31, 1996. Mean follow-up time was 11.1⫾4.0
years (range, 0.3 to 14.3 years). Mortality data were obtained from
the Mortality Register of the Swedish National Bureau of Statistics.
In 59% the cause of death was based on autopsy findings.
Stroke Rates
Cases of stroke were retrieved from the Stroke Registry of Malmö.16
Data linkage with the National Cause of Death Registry and the
Swedish Hospital Discharge Register was used for retrieval of
additional cases. Cases coded 430, 431, 434, or 436 according to the
International Classification of Diseases, Ninth Revision17 (ICD-9)
were counted as strokes. By definition, cases of transient ischemic
attacks (ICD-9 code 435) were excluded. The criterion for stroke
classified as ischemic stroke (ICD-9 code 434), subarachnoid hemorrhage (ICD-9 code 430), and intracerebral hemorrhage (ICD-9
code 431) was verification of the clinical presentation at CT, lumbar
puncture, or necropsy. In all, 56 (97%) of the cases were validated by
autopsy or studies of hospital records. Mean follow-up time to the
stroke event was 10.6⫾4.2 years (range, 0.3 to 14.3 years).
Statistical Analysis
The Mann-Whitney U test and Pearson’s ␹2 test were used for
comparisons of groups. The Kaplan-Meier method18 with Breslow
statistics was used for comparisons of stroke and survival rates in
relation to ECG findings. The Cox proportional hazard model19 was
used to adjust these associations for potential confounders. Significance testing (P⬍0.20) of the cardiovascular risk factors in categories of cardiac arrhythmias was used to identify potential confounders. The fit of the proportional hazard model was confirmed by
plotting the hazard functions in different categories of risk factors
over time.
Results
Stroke and Death Rates
Fifty-eight men suffered a stroke during the follow-up, 6 had
intracerebral hemorrhage (ICD-9 code 431), 36 an ischemic
stroke (ICD-9 code 434), and 16 had an unspecified stroke
(ICD-9 code 436). Eight (14%) of the subjects with strokes
died within 28 days. In all, 181 (45%) died during the
follow-up, 89 (49%) of them from cardiovascular disease
(ICD-9 codes 390 to 448).
Two hundred thirty-six men (58.7%) had hypertension
(ⱖ160/95 mm Hg or treatment). Forty-four of them had a
stroke (4 intracerebral hemorrhage, 27 ischemic strokes, and
13 unspecified strokes). Fourteen strokes (2 intracerebral
hemorrhage, 9 ischemic strokes, and 3 unspecified strokes)
occurred among men with normal blood pressure. Stroke and
death rates among men with hypertension were significantly
higher than they were among men with normal blood pressure
(stroke: 18.5 versus 7.5 per 1000 person-years, P⫽0.002;
mortality: 46.8 versus 32.3 per 1000 person-years, P⫽0.02).
Incidence of Stroke and Death in Relation to
Atrial and Ventricular Arrhythmias
Prevalence of men with AF, frequent AEB, and ventricular
arrhythmias in Lown class 2 to 5 in the entire cohort and
among men with hypertension is presented in Tables 1 and 2.
Rates of stroke were higher among men with a high frequency
of AEB (19.5 versus 11.6 per 1000 person-years; P⫽0.068)
and in men with AF (34.5 versus 11.6 per 1000 person-years;
P⫽0.007) than it was among men without frequent AEB or
AF (Table 1). Among men with hypertension, the stroke rates
were similarly higher among men with frequent AEB (32.3
versus 14.7 per 1000 person-years; P⫽0.01) and among men
Engström et al
Atrial Ectopic Beats and Risk of Stroke
2927
TABLE 2. Mortality and Stroke During 14 Years Among Hypertensive Men in Relation to Findings From a 24-Hour Ambulatory
ECG Recording
All-Cause Mortality
Stroke
n
Deaths,
n (%)
Total
Follow-Up, y
Deaths/
1000 PY
P
Events, n (%)
Follow-Up, y
Events/
1000 PY
P
183
85 (46)
2005
42.4
Reference
28 (15)
1907
14.7
Reference
44
27 (61)
455
59.3
0.24
13 (30)
402
32.3
0.01
9
7 (78)
80
87.2
0.04
3 (33)
74
40.7
0.03
Lown class 0–1
149
72 (48)
1650
43.6
Reference
24 (16)
1555
15.4
Reference
Lown class 2–5
87
47 (54)
891
52.8
0.19
20 (23)
827
24.2
0.39
236
119 (50)
2541
46.8
44 (19)
2382
18.5
Not AF or frequent AEB
Frequent AEB, not AF
AF
All hypertensive men
PY indicates person-years.
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with AF (40.7 versus 14.7 per 1000 person-years; P⫽0.03)
(Table 2). The increased stroke rate among men with arrhythmias in Lown class 2 to 5 was not statistically significant
(Tables 1 and 2).
Within the group with high frequency of AEB, the number
of premature beats was higher among those who had a stroke
during the follow-up (median number of AEB per 24 hours,
1988 [range, 272–12 355] versus 726 [range, 218 – 8152];
P⫽0.02). When the number of AEB among men with and
without stroke was studied in relation to the circadian
distribution, the difference in number of AEB was highest
between 12 and 6 PM (median number of cases, 1274 [range,
29 –3587]; controls, 151 [range, 6 –2358]; P⫽0.003) and
smallest between 0 and 6 AM (median number of cases, 242
[range, 8 –3013]; controls, 215 [range, 2–2328]; P⫽0.39).
Cardiovascular Risk Factors in Relation to
Occurrence of Arrhythmias
The distribution of cardiovascular risk factors in relation to
occurrence of cardiac arrhythmias is presented in Table 3.
There were no significant differences with regard to use of
antihypertensive medication, systolic blood pressure, mean
heart rate, smoking habits, alcohol consumption, plasma
cholesterol, diabetes, or history of angina pectoris (all
P⬎0.20) between men with and without a high frequency of
AEB. Diastolic blood pressure was lower among men with a
high frequency of AEB (90.7⫾10 versus 93.1⫾11 mm Hg;
P⫽0.16) than it was among men with a low frequency of
AEB. Distribution of cardiovascular risk factors in hypertensive men with and without a high frequency of AEB was also
similar.
Characteristics of Strokes With and Without
Frequent AEB
Twenty-eight-day case fatality rate after stroke showed no
significant differences between cases with and without frequent AEB (n⫽3 [20%] versus n⫽5 [13%], respectively).
Median time from the baseline examination to the stroke
event was 7.2 years (range, 0.4 to 13.8 years) among cases
with frequent AEB and 8.5 years (range, 0.6 to 13.5 years)
among cases without frequent AEB (P⫽NS). There was no
significant overrepresentation of ischemic strokes in the
group with high frequency of AEB.
With the purpose of exploring the extent to which strokes
with a high frequency of AEB at baseline had developed AF
TABLE 3. Distributions of Cardiovascular Risk Factors in Relation to AEB, AF, and
Lown Class
Frequent AEB
No
(n⫽311)
Yes
(n⫽77)
Lown Class
AF
(n⫽14)
0 –1
(n⫽259)
2–5
(n⫽143)
Blood pressure
Systolic
154⫾21
151⫾22
156⫾24
153⫾22
154⫾21
Diastolic
93.1⫾11
90.7⫾10
94.6⫾12
92.5⫾11
93.0⫾10
58 (19)
19 (25)
3 (21)
49 (19)
31 (22)
Antihypertensive medication, n (%)
␤-Blockers, n (%)
39 (13)
11 (14)
1 (7)
33 (13)
18 (13)
Hypertension (⬎160/95 mm Hg or treatment), n (%)
183 (59)
44 (57)
9 (64)
149 (58)
87 (61)
Digoxin medication, n (%)
25 (8)
8 (10)
14 (100)
16 (6)*
31 (22)*
Cholesterol, mmol/L)
6.0⫾1.0
6.0⫾1.1
5.5⫾0.71
6.0⫾1.1
6.0⫾1.0
53 (37)
Current smokers, n (%)
106 (34)
32 (42)
4 (29)
89 (34)
Diabetes, n (%)
16 (5)
3 (4)
2 (14)
11 (4)
10 (7)
Alcohol consumption ⬎250 g/wk, n (%)
29 (9)
6 (8)
0 (0)
18 (7)†
17 (12)†
Angina pectoris, n (%)
29 (9)
9 (12)
3 (21)
20 (8)*
21 (15)*
*P⬍0.05, †P⫽0.09 for Lown 0 –1 vs Lown 2–5.
2928
Stroke
December 2000
TABLE 4. Multivariate Analysis of Atrial Arrhythmias in Relation to Stroke and
All-Cause Mortality
All Men
Stroke
Not frequent AEB, no AF
Hypertensive Men
Mortality
Stroke
Mortality
Reference
Reference
Frequent AEB
1.9 (1.02–3.4)*
1.3 (0.88–1.8)
2.5 (1.3–4.8)†
Reference
1.3 (0.86–2.1)
Reference
Atrial fibrillation
3.2 (1.1–9.6)*
2.0 (1.04–3.8)*
3.2 (0.92–11.4)‡
1.6 (0.69–3.7)
Values are relative risks (95% CI), adjusted for systolic blood pressure, diabetes, history of angina
pectoris, and smoking.
*P⫽0.04, †P⫽0.009, ‡P⫽0.07.
at the time of the stroke event, the routine 12-lead resting
ECGs at the time of the hospital admission were investigated.
Among the 15 stroke patients who had frequent AEB at
baseline, 6 had AF at the time of stroke, 8 had sinus rhythm,
and in 1 case the resting ECG was unavailable.
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Multivariate Analysis
The increased incidence of stroke among men with high
frequency of AEB was statistically significant after adjustments for systolic blood pressure, history of angina pectoris,
smoking, and diabetes (all men: relative risk⫽1.9; 95% CI,
1.02 to 3.4; P⫽0.04; hypertensive men: relative risk⫽2.5;
95% CI, 1.3 to 4.8; P⬍0.01) (Table 4).
Discussion
As in many other studies, hypertension was associated with
an increased incidence of stroke. There were, however,
substantial differences between hypertensive men with and
without frequent AEB. A high frequency of AEB was
significantly associated with an increased risk. This association was independent of other major risk factors.
Associations between AF and stroke have been described
in many previous studies.1– 6 Left ventricular hypertrophy,
major T-wave inversion, and ST depression (ie, signs of
hypertension and ischemic heart disease) are other resting
ECG findings that have been associated with stroke.6,20 –24
However, few have studied incidence of stroke in relation to
24-hour ambulatory ECGs. Frishman et al9 reported significantly higher rates of cerebrovascular accidents among older
subjects with slow heart rate (⬍60 bpm) or AV block. No
significant association was found between cerebrovascular
accidents and AF, atrial tachycardia, or ventricular arrhythmias. However, subjects with previous myocardial infarctions
were included in their study, and the number of events was
smaller.
To the best of our knowledge, this is the first study
reporting frequent AEB to be an independent risk factor.
Although AEB often is considered a benign phenomenon, it
has been shown in clinical practice that frequent AEB could
be an early sign of heart failure and may precede AF.25
However, of the patients with frequent AEB at baseline, a
majority had sinus rhythm at the time of the stroke event.
Although it seems likely that a higher proportion developing
AF contributes to the increased risk among men with frequent
AEB, there also may be other explanations. Frequent AEB
could be a marker of other risk factors, eg, severe and
longstanding hypertension, asymptomatic atherosclerosis, or
structural abnormalities that cause embolism. Frequent AEB
could be a marker of mitral valve calcification or left atrial
enlargement, which in turn could cause increased thrombus
formation and embolism.26
In has been shown that frequent or complex ventricular
arrhythmias are common among older individuals both with
and without evidence of atherosclerotic disease.8 The associated prognostic significance of ventricular arrhythmias is
different, however, with increased mortality and cardiac
event rates if frequent arrhythmias occur in individuals with
atherosclerosis.8 Hypertensive men with frequent or complex
arrhythmias had higher rates of stroke in the present study.
This association did not reach significance, however.
Whether the absence of a significant association between
stroke and ventricular arrhythmias should be interpreted in
terms of lack of effect or lack of statistical power due to the
comparatively small number of individuals and events remains to be evaluated. With respect to AF, however, lack of
statistical power seems to be the most likely explanation for
the nonsignificant association, since only 14 men had AF
during the ECG recording.
Change of exposure during follow-up is a source of bias
inherent in all prospective studies of risk factors. Although
use of antihypertensive therapy showed small differences
between the groups at baseline, it is possible that men without
ECG abnormalities used antihypertensive drugs more often
during the follow-up. Even though this explanation seems
unlikely, it remains a potential confounder.
Vital status was updated by data linkage with the National
Cause of Death Registry. None was lost to follow-up. The
Stroke Registry of Malmö has continuously been recording
and validating all cerebrovascular events in Malmö since
1989. Ninety-seven percent of the cases were validated by
studies of hospital records or autopsy. The comparatively
high proportion of unspecified strokes could be explained by
the fact that CT scan was not performed on all patients during
the 1980s. According to other epidemiological studies from
the city, there is no reason to believe that biased retrieval or
validation of end points confounded the results.27
Frequent AEB assessed by means of 24-hour ECG monitoring was associated with stroke in this population-based
cohort of older men. We conclude that a high frequency of
AEB is associated with an increased incidence of stroke.
Acknowledgment
This study was supported by the Swedish Council for Social
Research.
Engström et al
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Cardiac Arrhythmias and Stroke: Increased Risk in Men With High Frequency of Atrial
Ectopic Beats
Gunnar Engström, Bo Hedblad, Steen Juul-Möller, Patrik Tydén and Lars Janzon
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Stroke. 2000;31:2925-2929
doi: 10.1161/01.STR.31.12.2925
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2000 American Heart Association, Inc. All rights reserved.
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