History of Parental Death From Stroke or Heart Trouble and the Risk of Stroke in Middle-aged Men
Background and Purpose The purpose of this study was to determine the effect of a history of parental death from stroke or heart trouble on the risk of major stroke events (fatal and nonfatal) in middle-aged British men.
Methods A prospective study was undertaken of 7735 middle-aged men, drawn at random from general practices in 24 British towns, who were followed up for an average of 14.8 (range, 13.5 to 16.0) years.
Results In the 7683 men providing information on at least one of their parents, there were 278 major stroke events and 947 major ischemic heart disease events. A history of death from stroke or heart trouble in mother or father was associated with a significantly increased risk of stroke independent of other risk factors, including hypertension. The association is due almost entirely to an increased risk of nonfatal stroke. In comparison with men whose parents were still alive or who had no history of parental death from either heart trouble or stroke, the adjusted relative risk of stroke in men with a history of parental stroke death was 1.4 (95% confidence interval [CI], 1.1 to 2.0; P=.02), and in men with parental heart trouble death, the relative risk was 1.3 (95% CI, 1.0 to 1.7; P=.04). The positive relationships were present whether the parental death occurred before or after 70 years of age. A parental death from stroke was not associated with increased risk of an ischemic heart disease event, although the latter was significantly associated with a history of parental death from heart trouble.
Conclusions Although factors such as hypertension and smoking are of major importance in the etiology of stroke, there is a link between a history of parental death from cardiovascular disease (stroke or heart trouble) and the risk of stroke that appears to be independent of the established risk factors.
There is a long history of concern regarding the possibility that a family history of stroke may be an important risk factor for stroke.1 Several epidemiological studies have examined this issue but with inconsistent results.1 2 3 4 5 6 7 8 9 10 11 12 It has been suggested that the inconsistencies may be due to weaknesses in study design, ascertainment of family history,11 12 13 and inclusion of different subtypes of stroke.13 Definition of family history has varied between studies, and even in purely genetically inherited diseases, different types of relatives (eg, siblings and parents) may show different levels of disease risk. Consequently, consistency between family histories using different types of relatives should not be expected. It has also been shown that recall bias may exist in case-control studies.14 Data from prospective studies are limited and many involve relatively small numbers of cases, but three of the four prospective studies have suggested a positive relationship between family history of stroke and risk of stroke.5 6 7 11 We examined the relationship between reported parental death from cardiovascular disease and the risk of stroke in a large prospective study of cardiovascular disease.
Subjects and Methods
The British Regional Heart Study is a large prospective study of cardiovascular disease comprising 7735 men aged 40 to 59 years selected from the age-sex registers of one group general practice in each of 24 towns in England, Wales, and Scotland (78% response rate). The criteria for selecting the towns, the general practices, and the subjects, as well as the methods of data collection, have been reported.15 Research nurses administered to each man a standard questionnaire that included questions on smoking habits, alcohol intake, physical activity, and medical history. Several physical measurements were made, and blood samples (nonfasting) were taken for biochemical and hematologic measurements. Classification methods for smoking status, alcohol consumption, occupation (social class), and body mass index have been reported.15 The men were classified according to their current smoking status into six groups: those who had never smoked cigarettes, ex–cigarette smokers, and four groups of current smokers (1 to 19, 20, 21 to 39, and ≥40 cigarettes per day). Those who had only ever smoked a pipe and/or cigars were grouped as “never smoked.” Ex–cigarette smokers who currently smoked a pipe or cigars were grouped as ex-smokers. Alcohol consumption was recorded using questions on frequency, quantity, and type, similar to those used in the 1978 General Household Survey. The men were classified into five groups on the basis of weekly intake: none, occasional, light, moderate, and heavy.16 Heavy drinking was defined as drinking more than 6 units (1 UK unit=8 to 10 g alcohol) daily or on most days. The men were asked to indicate their usual pattern of physical activity, and a physical activity (exercise) score was derived for each man on the basis of frequency and type (intensity) of the physical activity.17 The men were grouped into six broad categories on the basis of their total score: inactive, occasional, light, moderate, moderately vigorous, and vigorous.
Each man was asked at screening whether his father was alive and, if not, what he had been told was the cause of his father's death. This was classified as heart trouble, high BP, stroke, respiratory disease, cancer of the lung, other cancer, accident or injury, other specific causes, and cause unknown. The men were also asked the age of their fathers at death or, if the father was alive, his current age. Similar questions were asked relating to the mother. Information on both father's and mother's status was not obtained from 52 men.
The London School of Hygiene sphygmomanometer was used to measure BP twice in succession with the subjects seated and with the arm supported on a cushion. The mean of the two readings was used in the analysis, and all BP readings were adjusted for observer variation within each town.18 Men with adjusted SBP ≥160 mm Hg or adjusted DBP ≥90 mm Hg or subjects on regular antihypertensive treatment were regarded as hypertensive.
Preexisting IHD and Stroke
The men were asked whether a doctor had ever told them that they had angina or myocardial infarction (heart attack, coronary thrombosis), stroke, and a number of other disorders. The WHO (Rose) chest pain questionnaire19 was administered to all men at the initial examination, and an orthogonal three-lead ECG was recorded at rest.
Evidence of a previous stroke was determined by the subject's recall of such a diagnosis having been made by a doctor. There were 52 such men in the study.
Ischemic Heart Disease
The men were separated into three groups according to the evidence of IHD at screening: (1) no evidence of IHD on WHO chest pain questionnaire or ECG and no recall of a doctor diagnosis of IHD; (2) men with evidence suggesting IHD short of a definite myocardial infarction (this group contained those with ECG evidence of possible or definite myocardial ischemia or possible myocardial infarction [asymptomatic], those with angina or a possible myocardial infarction on WHO [Rose] chest pain questionnaire, or those with recall of a doctor diagnosis of angina [symptomatic]); and (3) men with a previous definite myocardial infarction on ECG or who recalled a doctor diagnosis of a myocardial infarction (“heart attack”).
All men were followed up for all-cause mortality and for cardiovascular morbidity.20 All stroke events occurring in the period up to December 1993 were included in the study, an average follow-up of 14.75 years (range, 13.5 to 16.0 years); follow-up was achieved for 99% of the cohort. Information on death was collected through the established “tagging” procedures provided by the National Health Service registers in Southport (England and Wales) and Edinburgh (Scotland). Nonfatal stroke events were those that produced a neurological deficit that was present for more than 24 hours. Evidence regarding such episodes was obtained from reports from a general practitioner, from semiannual reviews of the patients' notes through to the end of the study period, and from personal questionnaires sent to surviving subjects at the 5th and 12th years after initial examination. A diagnosis of stroke was not accepted on the basis of personal questionnaire data unless confirmed in the primary care records. Fatal stroke episodes were those coded on the death certificate as International Classification of Diseases codes 430 to 438. All death certificates in which it appeared that coding as stroke was not appropriate, or in which stroke was not the attributed code when it might have been, were explored by correspondence with the certifying doctor and the hospital concerned. No information on the type of stroke was available.
The Cox proportional-hazards model was used to assess the independent contributions of parental status to the risk of stroke and to obtain the RRs for parental status adjusted for age and the other risk factors.21 In the adjustment, age and SBP were fitted as continuous variables. Alcohol (five levels), smoking (six levels), physical activity (six levels), social class (three groups), diabetes (yes/no), and preexisting IHD on questionnaire or ECG (three levels) were fitted as categorical variables.
During the mean follow-up period of 14.8 years, there were 278 major stroke events (63 fatal and 215 nonfatal) in the 7683 men who provided information on at least one of their parents, a rate of 2.7 per 1000 person-years. Because of the interest in men with parental history of cardiovascular disease, eg, history of parental stroke or heart trouble, the men were divided into four groups on the basis of their parents' status: (1) both parents alive, (2) neither parent died of heart trouble or stroke, (3) either parent died of heart trouble, and (4) either parent died of stroke. Those who reported one parent dying of stroke and one parent from heart trouble were classified into group 4. The four groups are thus mutually exclusive. Table 1⇓ shows the stroke rate per 1000 person-years for the four groups. Men who had a history of parental stroke death had the highest rate, followed by men with a history of parental heart trouble death. Both these groups had higher rates than men in whom both parents were alive, as well as men in whom neither parent had died from heart trouble or stroke. Those whose parents were both alive had the lowest rate, largely due to the fact that men whose parents were both alive were significantly younger. After adjusting for age, a history of parental heart trouble death or stroke death was associated with a significant increase in RR compared with the group of men in whom both parents were alive (RR, 1.7; 95% CI, 1.0 to 2.9 [P=.04] and RR, 1.9; 95% CI, 1.1 to 3.3 [P=.02], respectively) and compared with those in whom neither parent had died of heart trouble/stroke (RR, 1.4; 95% CI, 1.0 to 1.8 [P=.03] and RR, 1.5; 95% CI, 1.1 to 2.1 [P=.01], respectively). Men whose parents died from other causes showed slightly higher risk than those whose parents were both alive (nonsignificant). Within this former group, there were only 74 men with parental history of death from high BP, and these men showed a risk of stroke similar to that of men who reported parents dying from other causes.
Cardiovascular Risk Factors
Table 2⇓ shows the levels of cardiovascular risk factors by the four parental status groups adjusted for age. Those who reported history of parental stroke death or heart trouble death had significantly higher mean SBP and DBP, higher rates of antihypertensive treatment, and higher mean body mass index and cholesterol than men whose parents were alive or men whose parents had died of other causes. They were more likely to be nonmanual workers compared with those whose parents died of other causes, but they showed similar rates of current smoking. Prevalence of definite myocardial infarction was significantly higher in men with parental history of heart trouble death, but men with parental history of stroke death showed rates of definite myocardial infarction similar to those whose parents were alive or who died of other causes. There was no significant difference in the rate of heavy drinking, physical activity, prevalence of IHD (group 2), history of stroke, or diabetes among the four groups.
The increased mean level of SBP in men with history of parental heart trouble or stroke death remained significant after adjustment for body mass index, alcohol intake, and social class, factors associated with BP.
Because men in whom neither parent had died of heart trouble or stroke showed no significant difference in risk of stroke from those men whose parents were alive, we combined these two groups as the reference group. To illustrate the effects of potential confounders and because hypertension may be the causal pathway, we examined the relationship between history of parental death and stroke, adjusting first for age and then in addition for social class, smoking, physical activity, alcohol intake, recall of stroke, diabetes, and preexisting IHD, all known risk factors for stroke. Adjustments for these factors made little difference to the relationships (Table 3⇓). To see whether the increased risk may be mediated by BP, we adjusted also for SBP and use of antihypertensive treatment. The increased risk was attenuated but remained significantly increased (P=.04 and P=.02 for history of parental heart trouble and stroke, respectively).
Because those subjects recalling a doctor's diagnosis of stroke or IHD or taking antihypertensive drugs may be more likely than others to recall the cause of death of their parents, the analysis in Table 3⇑ was repeated excluding all men with history of stroke or IHD or who were receiving antihypertensive treatment. Exclusion made little difference to the relationships seen in Table 3⇑.
Maternal and Paternal History
Because it has been suggested that history of maternal death from stroke is the more important predictor of stroke,6 we also examined the separate influence of a history of maternal and paternal stroke deaths. The relationship between parental status and risk of stroke was seen for both maternal and paternal history. In men who had a history of maternal stroke death (n=545), the rate per 1000 person-years was 4.0, and in men who had a history of paternal stroke death (n=515), the rate was 3.8 per 1000 person-years. Only 58 men reported both parents having died of stroke, with one stroke event in this group. In comparison with those men whose parents were alive or who died of other causes, history of paternal stroke was associated with an RR of 1.5 (95% CI, 1.0 to 2.2), and history of maternal stroke was associated with an RR of 1.6 (95% CI, 1.0 to 2.4) after adjustment for the confounding variables, excluding hypertension. Further adjustment for SBP and use of antihypertensive treatment reduced the risk slightly (history of paternal stroke death: RR, 1.4; 95% CI, 0.9 to 2.0; maternal stroke death: RR, 1.4; 95% CI, 0.9 to 2.0).
Age of Parental Death
To assess whether the age at which parents die may play a role, we divided the men who reported parental death from heart trouble or stroke into those whose parent(s) died before age 70 and those whose parent(s) died at or after age 70 (Table 4⇓). Men whose mother and/or father died of heart trouble or stroke had higher RRs than men whose parents were alive or died of other causes irrespective of age at death, although those whose parents died of stroke before age 70 had the highest RR. Those in whom at least one parent died of heart trouble before age 70 had higher risk than those whose parents died of heart trouble after age 70, but the difference was not significant. These relationships persisted even after adjustment for potential confounders (excluding SBP and use of antihypertensive drugs). Men whose parents died of heart trouble before age 70 showed significantly higher age-adjusted mean SBP than those whose parents died of heart trouble after age 70 (147.8 versus 144.5 mm Hg; P<.01). Similarly, men whose parents died of stroke before age 70 showed significantly higher mean SBP than those whose parents died of stroke after age 70 (148.8 versus 145.7 mm Hg; P<.01). Additional adjustment for SBP further reduced the increased risk in those whose parents died before age 70.
We also examined the relationship between parental death from heart trouble or stroke by levels of established risk factors for stroke such as age, hypertension, and smoking (Table 5⇓). The increased risk of stroke associated with parental death from stroke was evident in the older men (50 to 59 years) but was not seen in the youngest group (40 to 49 years old). It was more apparent in normotensive subjects and was seen in both nonsmokers and current smokers. Parental death from heart trouble was associated with increased risk of stroke at all levels of risk factors, although it was most apparent in the oldest age group (55 to 59 years), in normotensive subjects, and in nonsmokers. However, a test for interaction did not show any significant difference in the relationship between parental death from stroke or heart trouble and risk of stroke by the levels of these risk factors.
Fatal and Nonfatal Strokes
We also examined the relationship between parental status and fatal (n=63) and nonfatal (n=215) strokes separately. No association was seen between parental status and fatal stroke cases. The age-adjusted RRs were 1.0, 1.0, and 0.8 for those with no parental history of heart trouble/stroke, history of parental heart trouble, and history of parental stroke, respectively. The association with stroke events was almost entirely due to nonfatal strokes, with age-adjusted RRs of 1.0, 1.5 (95% CI, 1.3 to 2.0), and 1.9 (95% CI, 1.3 to 2.6), respectively.
History of Parental Stroke and Heart Trouble Death and Risk of Coronary Heart Disease
In this cohort of men, we have previously shown that a history of parental death from heart trouble is associated with increased risk of IHD.22 We have now examined the relationship between history of parental death from heart trouble or stroke and the risk of major IHD events. There were 947 major IHD events (fatal and nonfatal). History of parental death from heart trouble is significantly associated with increased risk of IHD after adjustment for age (RR, 1.5; 95% CI, 1.3 to 1.7). The increased risk remained even after adjustment for SBP and other potential confounders (RR, 1.4; 95% CI, 1.2 to 1.6). However, no significant association was seen between history of parental death from stroke and the risk of coronary heart disease (age-adjusted RR, 1.2; 95% CI, 0.9 to 1.4).
The findings in this study suggest that history of parental death from heart trouble or stroke is associated with an increased risk of stroke independent of SBP and other established risk factors. The association was seen for both paternal and maternal history of stroke death, and age of the parent at death appeared to have no appreciable effect. The positive association seen cannot be due to recall bias (ie, that patients with stroke are more likely to recall family history than those without stroke) because information on parental status was obtained before the stroke event.
Validity of Reporting
This study is based on reported history of parental death from stroke, and we have not included parents who may have suffered from stroke and survived or died later from other causes. This is likely to lead to an underestimation of the risk associated with parental history of stroke. Similarly, inclusion in the comparison group of men whose parents were still alive and may subsequently die of stroke, as well as men who did not know the cause of their parents' deaths, could lead to an underestimation of the effect of history of parental stroke. This has been demonstrated in the Framingham study, in which history obtained from parents' death certificates failed to show any association with risk of stroke. However, when history based on both fatal and nonfatal confirmed events in parents was used, a positive association was seen.11 Although no validation of reporting of stroke was carried out in the present study, validation of reporting of parental death from heart trouble carried out in a sample of 81 parents showed that if a man reported heart trouble as being the cause of his parent's death, it is likely that the parent died from heart trouble.22
Previous Prospective Studies
In the Rancho Bernado Study, family history of stroke in first-degree relatives was associated with increased risk of stroke deaths in women but not in men.5 In a Swedish study, history of maternal but not paternal stroke death was associated with a threefold increase of stroke events in men independent of levels of BP, fibrinogen, and obesity.6 In the Framingham Study, history of maternal and paternal stroke events was associated with an increased risk of stroke events among Offspring members of those whose parents had confirmed history of stroke.11 However, no association between history of parental stroke events was reported in a 5-year follow-up of men and women in the Copenhagen Study.7 The inconsistencies between all these studies may be due to the differing ascertainment of family history, the small number of cases involved, or in some studies, the inclusion of fatal stroke outcome only.
Possible Genetic Factors
Family history of stroke has shown to be associated with an increase of BP,23 as has been observed in this study. Hypertension is considered to be partly genetically determined,24 and it has been suggested that BP may be the mediating factor in the familial effect on risk of stroke. Although adjustment for SBP and use of antihypertensive drugs partially explained the increased risk in this study, a significant 40% increase in risk remained, suggesting that other factors are operating. Although the increased risk may be due to residual confounding, given our measurement of adult BP on a single occasion, this seems unlikely since the influence of parental history of stroke was seen more strongly in normotensive subjects. Furthermore, history of parental stroke seems to add little to the prediction of stroke once hypertension is present, possibly because the absolute rate in the latter group is already considerably raised. It is not clear whether the effect operates through familial environmental factors not measured in this study (eg, diet) or through a genetic component of increased susceptibility to stroke. Homocysteine levels are independently associated with stroke risk,25 and it is possible that some of the familial association demonstrated in our own study is due to an underlying inheritance of genes associated with β-synthetase production and folic acid metabolism, which contribute to levels of homocysteine.
Studies of Twins
Studies of twins provide the strongest evidence of genetic predisposition. A study of stroke among male twins showed similar concordance in stroke deaths in monozygotic and dizygotic male twins.2 However, a recent US twin registry study strongly suggests a genetic component because the concordance of stroke rates was four times higher in monozygotic than in dizygotic twins.10 This last study examined fatal and nonfatal stroke cases, whereas the earlier study examined only fatal events on the basis of death certificates.
Subtypes of Stroke
Although we do not have information on subtypes of stroke in this study, about 85% of strokes in adults in Great Britain are ischemic (thromboembolic), with only about 15% attributable to intracerebral or subarachnoid hemorrhage.26 It is likely that studies examining fatal events only would tend to have a higher ratio of hemorrhagic to ischemic stroke because the former have a higher case fatality. Consequently, failure to find relationships between history of parental stroke and fatal stroke may reflect the different etiology of hemorrhagic compared with thromboembolic stroke. In our data, the relationship between paternal history and stroke was apparent among older (50 to 59 years) rather than younger men (40 to 49 years), and since the ratio of hemorrhagic to thrombotic stroke declines with increasing age, this suggests that paternal history is more likely to be associated with thrombotic than hemorrhagic stroke. However, family history has also been associated with subarachnoid hemorrhage,27 although these subjects may have a very different pathophysiology. It is possible that a genetic effect is operating to make strokes more likely but not sufficiently severe to cause death. This possibility is supported by the finding in this study that family history of stroke was only associated with nonfatal events and not with fatal events. This may also explain the negative findings of studies in which only fatal stroke events have been examined.
Parental Death From Heart Trouble
We also observed increased risk of stroke in men with history of parental death from heart trouble. Although it is possible that individuals may confuse heart trouble and stroke in their process of recall, the specific association seen for stroke and not for coronary heart disease in men with history of parental stroke makes this seem unlikely. In contrast, men with history of parental heart trouble showed significantly increased risk of both stroke and coronary heart disease. Few studies have examined the influence of parental history of heart trouble in relation to stroke. In a recent matched community-based case-control study, it was also seen that history of IHD was more common in stroke patients than in control subjects.12 It is well recognized that history of parental heart trouble is associated with increased risk of coronary heart disease. The increased risk in this study seen for both IHD and stroke in men with history of parental death from heart trouble suggests that a history of parental death from heart trouble is associated with the development of IHD, which increases the susceptibility to stroke in later life. This is supported by the fact that the increased risk of stroke in men with history of parental heart trouble was only evident in the oldest men (55 to 59 years), whereas for men with history of parental death from stroke, the increase was evident at a younger age.
In the majority of prospective studies, investigators have compared subjects with a history of parental stroke with those with no history of parental stroke. If history of parental heart trouble indeed showed similar increased risk and constituted a large proportion of those classified as having no family history of stroke, inclusion of these men in the reference group would cause considerable underestimation of the influence of history of parental stroke.
Public Health Implications
Control of hypertension and smoking cessation are the current key recommendations to prevent stroke in middle-aged and elderly subjects.28 There is also evidence to support the maintenance of regular physical activity as a preventive measure.29 Although a history of parental death from stroke or heart trouble is not a modifiable factor, its presence should arouse individual concern to properly manage existing risk factors such as hypertension and smoking. To this end, health promotion material should include mention of parental history as indicating increased risk of stroke. Physicians should also be aware that the control of risk factors in such patients should be more rigorous than usual.
In this representative cohort of middle-aged British men, a history of death from stroke or heart trouble in a mother or father of any age is associated with a significantly increased risk of stroke independent of other risk factors, including hypertension. Although factors such as hypertension and cigarette smoking are of major importance in the etiology of stroke, the findings in this study suggest a link between parental death from cardiovascular disease and risk of stroke that appears to be independent of the established risk factors.
Selected Abbreviations and Acronyms
|DBP||=||diastolic blood pressure|
|IHD||=||ischemic heart disease|
|SBP||=||systolic blood pressure|
|WHO||=||World Health Organization|
The British Regional Heart Study is a British Heart Foundation (BHF) Research Group and receives support from the Stroke Association and the Department of Health. Dr Wannamethee is a BHF research fellow.
- Received February 15, 1996.
- Revision received May 6, 1996.
- Accepted May 9, 1996.
- Copyright © 1996 by American Heart Association
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