(Stroke. 2000;31:2925.)
© 2000 American Heart Association, Inc.
Original Contributions |
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 Gunnar.Engstrom{at}smi.mas.lu.se
| Abstract |
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MethodsThe
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 (
160/95 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,
218 AEB per 24
hours).
ResultsFifty-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.
ConclusionsA high frequency of AEB is associated with an increased incidence of stroke.
Key Words: arrhythmia cerebrovascular disorders electrocardiography
| Introduction |
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"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 |
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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 12x26-cm rubber
cuff. Men with systolic blood pressure
160 mm Hg or
diastolic blood pressure
95 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
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
7.0 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,
720 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
25%, 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,
218 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 Pearsons
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 |
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Two hundred thirty-six men (58.7%) had hypertension
(
160/95 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 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
).
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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, 27212 355] versus 726 [range, 2188152]; 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, 293587]; controls, 151 [range, 62358]; P=0.003) and smallest between 0 and 6 AM (median number of cases, 242 [range, 83013]; controls, 215 [range, 22328]; 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.
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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 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.
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
).
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| Discussion |
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Associations between AF and stroke have been described in many previous studies.1 2 3 4 5 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 21 22 23 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.
| Acknowledgments |
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Received May 25, 2000; revision received September 6, 2000; accepted September 6, 2000.
| References |
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