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(Circulation. 1996;94:2877-2882.)
© 1996 American Heart Association, Inc.

Articles

Body Height, Cardiovascular Risk Factors, and Risk of Stroke in Middle-aged Men and Women

A 14-Year Follow-up of the Finnmark Study

Inger Njølstad, MD; Egil Arnesen, MD; Per G. Lund-Larsen, MD, PhD

the Institute of Community Medicine, University of Tromsø, Norway (I.N., E.A.), and National Health Screening Service, Oslo, Norway (P.G.L.-L.).

Correspondence to Dr Inger Njølstad, Institute of Community Medicine, University of Tromsø, N-9037 Tromsø, Norway. E-mail ingern@ism.uit.no.

	Abstract

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Background Geographical differences in stroke mortality are not fully explained by population variations in blood pressure and antihypertensive treatment. Some studies have suggested that factors connected with health and nutrition in early life may be related to stroke morbidity and mortality. Body height is a sensitive marker for socioeconomic conditions, but results are conflicting as to whether height is associated with stroke.

Methods and Results In a population-based study, we investigated stroke incidence in relation to height and classic cardiovascular risk factors. A total of 13 266 men and women 35 to 52 years of age were followed for 14 years, and 241 first events of stroke were registered. Stroke incidence was 36% higher in men. Height was inversely related to stroke in a dose-response manner. Per 5-cm increase in height, the age-adjusted risk of stroke was 25% lower in women (P<.0001) and 18% lower in men (P=.0007). Systolic blood pressure and daily smoking were positively associated with stroke in both sexes, while serum triglyceride level was a significant risk factor in women only (relative risk per 1 mmol/L, 1.3; 95% CI, 1.1 to 1.5). The associations remained after adjustment for possible confounders and were also observed in certain subtypes of stroke.

Conclusions The results are consistent with the theory that factors influencing early growth as well as adult lifestyle factors contribute to cerebrovascular disease in adult age.

Key Words: risk factors • stroke • epidemiology • cerebrovascular disorders

	Introduction

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Official Norwegian statistics show that stroke mortality is higher in northern Norway than farther south.¹ Curiously, there are no corresponding geographical differences in blood pressure distributions in the general population.² Additional stroke determinants that are unevenly distributed between the northern and southern regions therefore should be sought. One such factor is body height,³ which is determined both by genetics and by nutrition and health status in early life.⁴

Height is inversely associated with all-cause and cardiovascular mortality.⁵ In England, stroke mortality varies inversely with average body height in different regions,⁶ but the association between height and stroke is as yet not clarified.^{7 8 9 10 11 12 13 14 15} From observations in Norwegian counties, Forsdahl^{16 17} postulated poor childhood living conditions followed by prosperity to be associated with a high cardiovascular mortality in adult age. Studies from England and Wales support the view that unfavorable factors in fetal and infant life may be important for later coronary heart disease and stroke.¹⁸

In the present study we had the opportunity to assess height as a risk factor for stroke in addition to classic cardiovascular risk factors and ethnicity in a free-living population of more than 13 000 men and women who were 35 to 52 years old at study entry.

	Methods

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Study Population
In 1974, a cardiovascular disease study was initiated in Finnmark, the northernmost county in Norway. The survey was conducted by the National Health Screening Service in cooperation with the University of Tromsø and local health authorities.¹⁹ All resident men and women 35 to 49 years of age and a 10% random sample of those 20 to 34 years of age were invited through a personal, mailed letter. In four small municipalities, all residents 20 to 49 years of age were invited. Three years later, a nearly identical screening was carried out.² A total of 7073 men and 6339 women (90.5% of those invited) who were born from 1925 to 1942 attended one or both screenings. Both surveys comprised a questionnaire on cardiovascular history and symptoms, smoking habits, physical activity, and ethnicity. The questionnaire was to be filled in at home and was checked for consistency at the examination. Height was measured to the nearest centimeter and weight to the nearest half-kilogram. Blood pressure was measured twice with a mercury sphygmomanometer in sitting subjects and after 4 minutes' rest. Nonfasting total cholesterol, triglycerides, and glucose were determined in chilled sera. Serum HDL cholesterol was determined only at the second screening.²

The questionnaire used these questions to define ethnicity: "Are two or more of your grandparents of Saami origin?" and "Are two or more of your grandparents of Finnish origin?" Fifty percent were classified to be of Norse, 17% of Finnish, and 13% of Saami (Lappish) origin. The remaining persons were of Saami/Finnish (4%) or unknown (16%) ethnicity. In all, 77% of the subjects were born in Finnmark.

Follow-up and Case Identification
A total of 13 266 participants free from stroke at baseline and with a nonmissing value for height were followed; excluded were 16 men and 13 women with verified or possible stroke before screening. Mean follow-up was 14 years. First fatal or nonfatal stroke was the outcome measure.

Strokes were detected through hospital discharge diagnosis lists (International Classification of Diseases 8th and 9th revision codes 430-438) and through a systematic survey of the record files in the only two Finnmark hospitals. Deceased persons, with dates and causes of death, were identified by linkage to the Norwegian Registry of Deaths. A postal questionnaire to all 12 028 participants alive by June 1991 aimed to detect out-of-county and nonhospitalized events. The response rate was 81%. A total of 346 postal survey nonrespondents had moved from Finnmark during follow-up. Strokes among these (3% of the entire cohort) are likely to have been missed, while nonfatal cases among nonrespondents who resided in Finnmark throughout the follow-up period were detected through the hospital record surveys. Nonhospitalized events in the latter group may have escaped registration but are assumed to be very few in these young persons. If a death certificate, medical record, or postal survey response indicated a stroke, additional information was collected from hospitals and physicians for case verification and subtype classification of the first-ever stroke event. The World Health Organization definition of stroke was followed.²⁰ Strokes were classified as subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, or unclassified stroke. Cases with bloody spinal fluid but no further information to distinguish between subarachnoid or intracerebral hemorrhage (n=10) were included in the unclassified subgroup.

The validation process included inspection of medical records or discharge letters, autopsy reports, and radiograph and cerebral computer tomography descriptions. Eleven cases with a physician's diagnosis of stroke but inaccessible further medical information were included. One person did not give written consent for validation and was assigned as probable stroke. Not included as cases were 27 persons with some symptoms of stroke but with information suggestive of trauma or another disease.

The study was approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate. The State Health Directorate permitted access to medical record files.

Data Analysis
Incidence rates were based on the person-years from the date of the first screening attended until the first stroke, with the date of death from other reasons, emigration, or December 31, 1989, as censoring date. Age adjustment of incidence rates was performed by the direct method on 5-year age groups and with all attenders as the standard population. Age- and multivariate-adjusted relative risks were obtained from Cox proportional hazards analysis, in which these continuous variables were considered: age, systolic blood pressure, height and body mass index (weight/height² ), and serum total cholesterol, triglycerides, and glucose. Relative risks were determined for units arbitrarily chosen to approximate standard deviations for both sexes. Daily smoking (yes/no), self-reported diabetes (yes/no), medically treated hypertension (yes/no), and ethnic groups were included as covariates. In one analysis, height was examined by sex-specific quartiles. The numbers included vary slightly between individual analyses as the result of missing values. All significance tests were two-tailed, and significance level was chosen at 5%. The SAS statistical package version 6.09 was used.

	Results

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Baseline mean values and frequencies are given in Table 1. Serum lipids and blood pressure were higher in men, and more men were daily smokers. Large ethnic differences in height were observed. The differences in mean height between Saami (shortest) and Norse (tallest) men and women were 8.4 cm and 7.8 cm, respectively. The age distributions were similar in all ethnic groups.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics in Men and Women: The Finnmark Study, 1974-1989

During 187 336 person-years, 144 first-ever strokes among men and 97 first events among women were registered. Sex differences in stroke distribution were seen (Table 2). Almost 40% of the cases could not be subclassified.

View this table: [in this window] [in a new window]   Table 2. Distribution of Stroke Subtypes by Sex: The Finnmark Study, 1974-1989

Overall stroke incidence was 1.08 per 1000 person-years in women and was 36% higher among men (Table 3). Higher age-adjusted rates of stroke were observed among Finnish and Saami/Finnish men than among men of Norse origin, but the relative risks were only of borderline significance when controlled for height. In general, relative risks associated with ethnicity were attenuated once height was taken into account.

View this table: [in this window] [in a new window]   Table 3. Age-Adjusted Incidence Rates of Stroke per 1000 Person-Years, Relative Risks, and 95% CI by Ethnic Group and Sex: The Finnmark Study, 1974-1989

In both sexes, height, systolic blood pressure, and daily smoking were highly significant risk factors for stroke when adjusted for age (Table 4). The estimates changed only slightly when controlled for other variables. There was an apparent threshold level for smoking; incidence rates were similar in nonsmokers and smokers of <10 cigarettes per day (men, 1.1 per 1000 person-years; women, 0.8 per 1000 person-years). The incidence among smokers of 10 cigarettes was 1.8 per 1000 person-years in both men and women, with no additional risk increase among those who smoked 20 cigarettes (data not shown). Being treated for hypertension was a strong risk factor for men only. Body mass index was a highly significant predictor in the univariate but not the multivariate model. Few reported to be diabetics at baseline in this young cohort, but diabetes was nevertheless a strong risk factor among men, while serum glucose did not predict stroke in either sex. To examine the role of HDL cholesterol, a separate analysis was performed with the 1977 survey as baseline and with 5876 men (115 strokes) and 5410 women (67 strokes) in the cohort. Adjusted for all variables in Table 4 except triglycerides, a nonsignificant inverse relation was seen between serum HDL cholesterol and stroke in men (relative risk per 0.4 mmol/L increment in HDL cholesterol, 0.8; 95% CI, 0.6 to 1.0) and women (relative risk, 0.8; 95% CI, 0.6 to 1.1).

View this table: [in this window] [in a new window]   Table 4. Risk Factors for Stroke: Adjusted Relative Risks and 95% CI by Sex: The Finnmark Study, 1974-1989

Table 5 presents stroke in relation to sex-specific quartiles of body height. Controlled for age, ethnic group, and independent risk factors, an inverse association between height and stroke with a clear dose-response pattern was observed. The stroke risk was halved in the tallest compared with the shortest quartile among men and was reduced by 66% in women. The ² test for linear trend was highly significant in both sexes (P<.002).

View this table: [in this window] [in a new window]   Table 5. Age-Adjusted Incidence Rates of Stroke per 1000 Person-Years, Relative Risks, and 95% CI by Sex-Specific Quartiles of Body Height: The Finnmark Study, 1974-1989

Next, we examined the relation between several risk factors and stroke subtypes in four separate Cox analyses (Table 6). There were too few cases to warrant a sex-stratified subtype analysis. The multiple adjusted relative risks were virtually unchanged from relative risks adjusted only for age and sex (not shown). Height seemed inversely related to all stroke subtypes; the strongest relation was with intracerebral hemorrhage, while a borderline significance was seen for cerebral infarction and statistical significance was not reached for subarachnoid hemorrhage. Daily smoking was associated with a twofold-increased relative risk for all stroke subtypes except intracerebral hemorrhage. Also, daily smoking was the only variable significantly associated with subarachnoid hemorrhage. No significant relation was observed between total cholesterol and any stroke subtype, but the data suggested a positive association with cerebral infarction and a negative association with subarachnoid and intracerebral hemorrhage.

View this table: [in this window] [in a new window]   Table 6. Selected Risk Factors for Stroke Subtypes*: Adjusted Relative Risks and 95% CIs: The Finnmark Study, 1974-1989

Finally, we investigated risk factors for fatal stroke. Altogether, 23 men and 34 women died within 28 days after a first stroke. In all, 37 of these had a confirmed intracerebral or subarachnoid hemorrhage. In a Cox regression analysis as in Table 6, the relative risk associated with height was 0.64 (95% CI, 0.53 to 0.78). Daily smoking (relative risk, 3.06; 95% CI, 1.65 to 5.67) and systolic blood pressure (relative risk, 1.34; 95% CI, 1.09 to 1.65) were significant risk factors. Serum cholesterol was inversely related to fatal stroke (relative risk, 0.77; 95% CI, 0.61 to 0.95) (data not shown in table).

	Discussion

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Body height was a significant predictor of stroke in this population-based prospective study. The inverse relation between height and stroke was continuous, independent from obesity and classic cardiovascular risk factors, and observed in both sexes. In the tallest compared with the shortest quartiles, the risk of stroke was 55% lower among men and 66% lower among women. Our data suggest that the inverse relationship may hold for all subtypes of stroke except subarachnoid hemorrhage. Furthermore, blood pressure and cigarette smoking were significant independent predictors, whereas serum lipids and stroke were inconsistently related.

The population-based approach and the high attendance rate make selection bias unlikely. The follow-up on vital status was complete, and death certificate diagnoses were known for all deceased persons. A thorough search for fatal and nonfatal events was made in the hospitals serving the inhabitants of the county. The high response rate on the postal survey makes any large influence from missed nonfatal events unlikely, although 15% of the subjects moved from Finnmark during follow-up. If incidence rates of nonfatal stroke among postal survey responders are applied to the nonresponders, 28 cases would be expected among these persons. Actually, 28 cases were detected through the medical record surveys. Events in which a possible trauma or alternative disease could not be ruled out were not defined as cases. However, almost 40% of the strokes could not be subtype-classified because of nonperformed investigations or lack of detailed information, and the results should be interpreted in the light that "unclassified stroke" is a heterogeneous group in which intracerebral hemorrhages and cerebral infarctions probably make up different proportions in the two sexes.

Cardiovascular Risk Factors and Stroke
Daily smoking was a significant predictor of stroke in both sexes and for all subtypes except intracerebral hemorrhage. A positive relation between cigarette smoking and stroke was also seen in recent prospective studies among men¹² and women.²¹ Furthermore, our results are in line with a large meta-analysis²² that demonstrated that smoking in particular was associated with subarachnoid hemorrhage and cerebral infarction.

Systolic blood pressure has been a better stroke predictor than diastolic pressure in several studies.²³ We observed no sex difference in the relation between systolic blood pressure and stroke, but being treated for hypertension was a strong risk factor only for men. In the Copenhagen City Heart Study, the risk of stroke was 1.5 times higher among treated than among untreated subjects for a given systolic blood pressure with both sexes combined.²⁴

When controlled for other risk factors, no association persisted between serum total cholesterol and all stroke in either sex. Specified by stroke subtype, our data show an inverse relationship between serum cholesterol and subarachnoid as well as intracerebral hemorrhage and a positive relation with cerebral infarction. Though nonsignificant, these results are consistent with the large Multiple Risk Factor Intervention Trial²⁵ and other prospective studies of cholesterol and cerebral hemorrhages²⁶ and thromboembolic stroke^{26 27 28} and as reviewed by Qizilbash et al.²⁹ Controlled for confounders, serum triglyceride level was associated with stroke only in women, at variance with a Scandinavian study of mostly ischemic strokes.²⁸

Body Height and Stroke
To our knowledge, the Nurses' Health Study¹⁵ is the only previous study on the association between height and stroke in women and the only prospective study on height in relation to stroke subtypes. This large study found no association between height and stroke incidence or between height and stroke subtypes.¹⁵ However, no baseline biological measurements were undertaken, the study used self-reported height, and it was not population based. Results from studies among men vary. In a nested case-control study of stroke mortality, Paffenbarger and Wing⁷ found future cases to be on average 1 inch shorter than control subjects. Tverdal⁹ reported a significant inverse relation between height and stroke mortality in a follow-up study of 53 000 Norwegian middle-aged men, which included men from the present cohort. An inverse, however nonsignificant, relation between height and stroke incidence and mortality was observed in the Oslo study of men 40 to 49 years of age.¹² A large cohort study among American physicians found a small, nonsignificant decrease in stroke risk in the tallest compared with the shortest height quintile. No significant trend across height categories was seen.¹¹

What, then, could explain the inverse association between height and stroke in the present study? At least two different etiologic paths are conceivable. First, a short stature per se might physically increase the risk of stroke. Height is inversely associated with heart rate,³⁰ positively correlated to coronary artery lumen diameter,³¹ and could possibly affect stroke risk through physiological mechanisms, although we are not aware of any such evidence. Alternatively, the final attained height may be regarded as a marker of the sum of factors operating in early life, with some unfavorable factor related to height causing the association between adult height and stroke. Average body height reflects the socioeconomic level of a society.^{32 33 34} In individuals, height is both influenced by hereditary factors⁴ and associated with family economy in childhood³⁵ and with social class.^{36 37} Importantly, due to the finely tuned mechanisms of catch-up growth,³⁸ a permanent stunting of growth must be expected to have occurred either during a sensitive intrauterine or infant period or must be due to a prolonged period of poor nutrition or illness. Undernutrition during intrauterine life may permanently affect body size, and, depending on its timing, structures, metabolism, or hormonal activity.^{39 40}

Some evidence of an early life influence on stroke risk does exist. Forsdahl¹⁶ demonstrated a strong positive correlation between past infant mortality and adult stroke mortality among Norwegian men but not women. Current stroke mortality in England and Wales correlates with past neonatal rather than postneonatal mortality.⁴¹ The correlation was even stronger with past maternal mortality exclusive of puerperal fever,¹⁸ indicating a prenatal influence on later stroke risk.

Blood pressure and serum lipids are modifiable risk factors associated with adult lifestyle. However, in utero growth and adult blood pressure seem related,⁴² and increased blood pressure has been suggested as the physiological link between early living conditions and stroke risk in adult age.¹⁷ In our study, no baseline correlation between height and systolic blood pressure was observed in men (Pearson r=.003, P=.8052), and a weak but significant correlation was present in women (r=-.053, P<.0001). In both sexes, systolic blood pressure and height were highly significant independent predictors in the multivariate model, suggesting that they may influence the risk of stroke through different mechanisms.

Serum cholesterol in adults is associated with past infant mortality¹⁷ and with intrauterine growth.⁴³ An inverse relation between height and cholesterol was reported from a cohort of 19 000 adult men and women.³⁰ Serum cholesterol is positively associated with cerebral atherosclerosis,⁴⁴ but a low cholesterol concentration in blood and cell membranes may add to the fragility of small intracerebral vessel walls and contribute to the association between low serum cholesterol and intracerebral hemorrhage.⁴⁵ A protein-rich diet counteracts negative effects of salt on blood pressure and prevents stroke in stroke-prone rats,⁴⁶ and the declining stroke mortality in Japan seems closely related to postwar socioeconomic improvements, which include a diet with less salt and increased animal fat and protein content.^{34 45} Thus, a large body of evidence points to the importance of nutrition, whether it be during pregnancy, childhood, or adult age in stroke epidemiology.

We have no reason to believe that this study population is genetically predisposed for stroke. Stroke mortality shows a declining trend in Finnmark as in other Norwegian counties, although the mortality rates are higher.¹ Hereditary factors could possibly play a role in the observed association between height and stroke. It is not known to what extent the interethnic height differences in this population are due to genetics or to possible group-related differences in living conditions. Apparent ethnic differences in stroke were reduced when height was taken into account. The present cohort was born from 1925 to 1942. Living conditions in Finnmark, as indicated by infant mortality rates, lagged far behind the central areas of Norway throughout this period⁴⁷ and were probably tougher for the Saami and Finnish than for the average Norse population.¹⁷ The secular growth curve for army recruits from Finnmark born from 1925 to 1942 was steeper than for the whole country,⁴⁸ but even in those born as late as 1942 the mean height was 3.7 cm lower than the national average.³ One may speculate whether the socioeconomic conditions for this particular study population have allowed stroke determinants to come forward that will not be apparent in societies with more optimal conditions for pregnant women and children. Furthermore, if this reasoning is correct, the different selections of study participants may possibly explain some of the discrepancies between the findings on height and stroke in the present study in contrast to the two large cohort studies among US physicians¹¹ and nurses.¹⁵

Conclusions
Body height was negatively associated while blood pressure and daily smoking were positively associated with the risk of stroke in this cohort. It is suggested that a short stature is a marker for unfavorable conditions during early life that contribute to the risk of stroke, together with factors connected with adult lifestyle. Epidemiological studies of stroke are needed that more specifically address nutrition and other health factors in pregnancy, childhood, and adult age.

	Acknowledgments

 
This research was supported by the Norwegian Council on Cardiovascular Diseases and by the Norwegian National Programme for Health for All by the Year 2000 (Health and Inequities in Finnmark).

Received March 7, 1996; revision received June 18, 1996; accepted July 1, 1996.

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