CLINICAL STUDIES
Parental history of premature coronary heart disease mortality and signs of ischemia on the resting electrocardiogram
Dirk De Bacquer, MSca,
Guy De Backer, MD, PhD, FACCa,
Marcel Kornitzer, MD, PhD* and
Henry Blackburn, MD, PhD, FACC
a Department of Public Health, University of Ghent, Ghent, Belgium
* School of Public Health, Free University of Brussels, Brussels, Belgium
Division of Epidemiology, University of Minnesota, Minneapolis, Minnesota, USA
Manuscript received October 7, 1998;
revised manuscript received January 8, 1999,
accepted January 21, 1999.
Reprint requests and correspondence: Dr. Dirk De Bacquer, Department of Public Health, University of Ghent, De Pintelaan 185-Block A, B-9000 Gent, Belgium
dirk.debacquer{at}rug.ac.be
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Abstract
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OBJECTIVES
Here we explore the association between a family history of premature coronary heart disease (CHD) death and ischemic electrocardiogram (ECG) findings in the offspring.
BACKGROUND
In the general population, signs of ischemia are found on the resting ECG in about 10% of middle-aged men and women. Their independent predictive value for CHD morbidity and mortality has been shown in several studies.
METHODS
Our results are based on cross-sectional data from three large epidemiological studies performed in Belgium during the past two decades: the Belgian Heart Disease Prevention Project (n = 8,145), the Belgian Interuniversity Research on Nutrition and Health survey (n = 7,625) and the MONICA project (n = 3,193). A parental history of fatal CHD was considered premature if the father died from CHD before age 60 or the mother before age 70. Ischemic ECG findings were defined according to Minnesota Code criteria I1–3, IV1–3, V1–3 or VII1.
RESULTS
Subjects with a parental history of premature CHD death were found to have experienced significantly more frequently symptomatic CHD. After exclusion of symptomatic individuals, no major differences in lifestyle-related risk factors were found between the groups with and without a parental history of premature fatal CHD. After multivariate adjustment for age, smoking, body mass index and sex, the odds ratios (and 95% confidence interval [CI]) for ECG ischemia associated with a positive parental history of premature death were 1.42 (1.10–1.82), 1.47 (1.16–1.88) and 1.37 (0.78–2.41) in the three studies. Additional adjustment for systolic blood pressure, total cholesterol and, if available, lifestyle-related factors did not alter the magnitude of the odds ratios. Overall, in men aged 45 to 64 years, ECG ischemia was significantly more frequent (36% excess) in those with positive parental history.
CONCLUSIONS
Subjects in whom one or both parents died prematurely from cardiac-related diseases have signs of ischemia more frequently on their electrocardiogram, and this is independent of other risk factors.
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Abbreviations and Acronyms
| | AMI | = acute myocardial infarction | | BHDPP | = Belgian Heart Disease Prevention Project | | BIRNH | = Belgian Interuniversity Research on Nutrition and Health | | BMI | = body mass index | | CHD | = coronary heart disease | | ECG | = electrocardiogram, electrocardiographic | | HDL | = high-density lipoprotein | | ICD | = International Classification of Diseases | | MONICA | = Multinational Monitoring of Trends and Determinants in Cardiovascular Diseases |
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The role of the resting electrocardiogram (ECG) in the diagnosis and prognosis of coronary heart disease (CHD) is well recognized. The electrocardiogram has not only proved its value in clinical cardiology as a diagnostic tool to detect and follow the evolution of existing heart disease, but is also used in population-based studies as a screening method to detect subclinical disease and as a risk factor predicting CHD incidence and mortality (1–4).
A family history of heart disease has also been given increasing attention as a predictor of cardiovascular disease risk (5–32). In some studies, it was suggested that this factor works mainly through the major classical risk factors rather than independently. Until now, the association between this well-established risk factor and electrocardiographic abnormalities has not been studied. We pose the question whether familial clustering of CHD risk is also apparent in electrocardiography. Using data from several large epidemiological studies performed in Belgium in recent decades, we report here on the association between parental history of premature CHD and ECG ischemia.
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Methods
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Study populations.
Our results are based on data derived from three large epidemiological studies performed in Belgium in the past two decades: the Belgian Heart Disease Prevention Project (BHDPP) performed in the late 1970s, the Belgian Interuniversity Research on Nutrition and Health (BIRNH) survey done in the beginning of the 1980s and the MONICA project (Multinational Monitoring of Trends and Determinants in Cardiovascular Diseases) representing the end of the 1980s and the early 1990s.
The objective of the BHDPP, which was part of the WHO European Collaborative Trial (33), was to study the effect of a multifactorial intervention program for prevention of cardiovascular morbidity and mortality in a population of middle-aged working men (34). The data used in this analysis are those obtained at the final examinations of men aged 45 to 64 years gathered in the period 1978 to 1980. Information was obtained by validated self-administered questionnaires (including the Rose questionnaire), a standard clinical examination and a standardized electrocardiogram (using a 3-channel device, type 1516B; Hewlett-Packard, Palo Alto, California). The participation rate in the baseline examination of the BHDPP study was 71%. The vital status of both parents was obtained through a questionnaire. In case one or both of the parents had died, the cause and age of death was asked. For the purpose of the present study, we considered as death from CHD: coronary thrombosis, myocardial infarction, heart attack or sudden death. Parental history of premature CHD death was defined as positive if the father died from CHD before age 60 and the mother before age 70. In this report, all subjects for whom the vital status of the parents was unknown, and those whose father or mother died prematurely but with cause unknown (n = 2,116), were deleted from the analyses. Hence, a total of 8,145 records from the BHDPP study population were eligible for inclusion.
In contrast to the BHDPP study of working men, the BIRNH study was a population-based survey designed to study the association between nutritional patterns, clinical and biochemical characteristics and total and cause-specific mortality in men and women (35,36). A random age- and sex-stratified sample was selected from voting lists in 42 out of the 43 administrative districts in Belgium. The participation rate in this population-based study was 36%. Baseline data were gathered in the period 1980 to 1984, and included self-administered questionnaires, clinical examinations and a standardized ECG, adopting similar methodology, questionnaires and equipment as that in the BHDPP study. Hence, the definition of a parental history of premature fatal CHD is the same. After exclusion of records with insufficient information on parental status (n = 1,453) data on 3,974 men and 3,651 women aged 35 to 74 years were available for analysis.
The MONICA project was also a population-based study, concentrating on the trends in both incidence and risk factors of cardiovascular diseases (37). The Belgian collaborating MONICA center, Ghent-Charleroi, carried out three independent risk factor surveys (1985–86, 1988–89, and 1990–92) in the general population (38). For each survey, an age- and gender-stratified random sample of 2,000 subjects aged 25 to 64 years was selected in both provincial cities of Ghent and Charleroi. Combining the three surveys, the participation rate was 53% in Ghent and 37% in Charleroi. All medical examinations, including an ECG, were performed according to the MONICA protocol. The vital status of the parents was obtained using a self-administered questionnaire, and causes of death were classified according to International Classification of Diseases (ICD) criteria. For the present study, cases of CHD mortality were defined as those with ICD codes 410-414 or 798 (sudden death). Again, parental CHD death was defined as premature if the father died from CHD before age 60 and/or the mother before age 70. The same exclusion criteria as mentioned earlier were used (n = 576 records deleted), resulting in 1,650 men and 1,543 women aged 35 to 64 years eligible for inclusion in our analyses.
Definition of CHD risk factors.
All variables considered in the present study were consistently defined in all three studies. Age was defined as the subjects’ age at the time of medical examination. Smoking was defined as current cigarette smoking and body mass index (BMI) was calculated as the weight (kg) divided by height squared (m2). Polyunsaturated-to-saturated fat intake ratio (P/S ratio) in the BIRNH survey and alcohol consumption in both BIRNH and MONICA studies were obtained using 24-h food questionnaires. Hypertension was defined according to the WHO definition as: systolic blood pressure  160 mm Hg and/or diastolic blood pressure 95 mm Hg and/or currently under antihypertensive drug treatment. High blood cholesterol level was defined as a total cholesterol value equal to or more than 250 mg/dl. Signs of ischemia on the baseline ECG were defined according to the Minnesota Codes (39) I1–3 (Q wave abnormalities), IV1–3 (significant or borderline ST segment depression), V1–3 (deep or moderate T wave inversion) or VII1 (complete left bundle branch block). All ECGs in the three studies were read and coded by the same cardiologist (M.K.). Symptomatic CHD was defined as either angina pectoris or a history of acute myocardial infarction according to the Rose questionnaire (40). Analyses of the association between ischemic ECG findings and parental history of premature fatal CHD are based on all subjects free of symptomatic CHD at baseline.
Statistical methods.
Age standardization of CHD risk factors was performed according to the direct method (41), using five-year age strata and the male and female Belgian population of January 1, 1991 as reference. The distributions of lifestyle characteristics according to parental history of premature CHD death were compared according to the Mann-Whitney U test for continuous variables and Fisher exact test for proportions. The associations between parental history of premature fatal CHD and risk factors for CHD were expressed by odds ratios. To estimate the precision and statistical significance of these odds ratios, 95% confidence intervals are given. Odds ratios were multivariately adjusted using logistic regression analysis. All statistical analyses were performed with SAS software (42). A level of alpha = 0.05 was used to indicate statistical significance.
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Results
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In Table 1, the distributions of parental history of fatal CHD are shown by age and gender for the three studies separately. The age-standardized prevalences in the subgroup of middle-aged subjects are 9.4% (BHDPP), 10.0% (BIRNH) and 4.5% (MONICA) in men, and 10.0% (BIRNH) and 6.1% (MONICA) in women, indicating the similarity of these prevalence rates between the sexes and partly reflecting the downwards trend in fatal CHD events during the last decades. Grouping all men aged 45 to 64 from the three databases revealed an age-standardized prevalence rate of 9.1%. The prevalences of symptomatic CHD in the study subjects themselves are given in Table 2, showing the same downwards trend over the three studies again with comparable figures in men and women. In the combined group of all 45- to 64-year-old men, the age-standardized prevalence rate of symptomatic CHD was 10.8%.
Association between parental history of premature CHD mortality and prevalence of symptomatic CHD.
The association between premature CHD mortality in parents and the prevalence of symptomatic CHD in their offspring is quantified in Table 3 using odds ratios adjusted for age, smoking, BMI, gender and study, shown with 95% confidence intervals to evaluate statistical significance. From this table, we conclude that the association is strong. Odds ratios for symptomatic CHD are rather comparable among the three studies. Their statistical significance varies with the size of the studies (e.g., MONICA study) and with the prevalence of the outcome under study (e.g., history of acute myocardial infarction [AMI]). In the group of middle-aged men, adjusted odds ratios are 1.51 (1.17–1.96) for history of acute myocardial infarction, 1.62 (1.29–2.06) for angina pectoris and 1.64 (1.36–1.99) for either form of symptomatic CHD. Hence, men with a father or mother who died prematurely of CHD have 64% excess of CHD compared with those men whose parents did not die prematurely from CHD.
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Table 3 Association Between Parental History of Premature CHD Death and CHD in the Offspring in the Three Studies
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Association between parental history of premature CHD mortality and ischemic ECG findings in asymptomatic subjects.
To study the association between fatal CHD in parents and ischemic electrocardiographic findings in their offspring free of CHD, we excluded the 1,701 men and women who suffered from symptomatic CHD. In Table 4, lifestyle characteristics are shown in this group of asymptomatic subjects, according to their status of parental history of premature CHD mortality. The distributions of age, BMI and smoking showed similar characteristics between groups. Only the proportion of women in the MONICA study was highly significantly different between groups. The BIRNH and MONICA database allowed us also to compare lifestyles between groups in more detail, including information available on alcohol consumption and polyunsaturated-to-saturated fat intake (BIRNH only). The result was that the distribution of P/S ratio in diet was comparable between groups and that the group where either a father or mother died prematurely from CHD consumed on average about the same amount of alcohol as the control group (the difference was borderline significant in the BIRNH survey).
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Table 4 Lifestyle Characteristics According to Parental History of Premature CHD Death in Subjects Free of CHD in the Three Studies
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Table 5 shows the age-standardized prevalences of primary CHD risk factors in the male subgroups aged 45 to 64, from all three databases. The prevalence of hypertension in the MONICA study, reflecting the end of 1980, is much lower than that observed in the BHDPP study, carried out in the end of the 1970s. The data from the BIRNH study suggest that this time-trend was linear, because its prevalence is intermediate. For hypercholesterolemia and ECG ischemia, however, the prevalences in middle-aged men seem to remain rather stable for the decades preceding the 1990s.
We find that parental history of premature CHD mortality results in excess cardiovascular risk in their offspring. As seen in Table 6, sons and daughters of parents who died prematurely of CHD had much higher risk for being themselves hypertensive, especially in the BIRNH and MONICA databases, with multivariately adjusted odds ratios of 1.53 (1.26–1.85) and 1.71 (1.12–2.62), respectively. Although less pronounced and not reaching the limit of statistical significance, these offspring are moreover at elevated risk of having high serum cholesterol concentrations, especially in the BIRNH study, where an odds ratio of 1.27 (1.06–1.52) was observed. Finally, subjects having one or both parents who died prematurely from CHD were more likely to show ischemic abnormalities on their resting ECG, with very similar odds ratios in the three databases under study here. After adjustment for age, BMI, smoking, gender, systolic blood pressure, total cholesterol and, for the BIRNH study, diabetic status, alcohol consumption and P/S ratio in diet, these odds ratios were 1.35 (1.04–1.74) in the BHDPP study, 1.40 (1.10–1.80) in the BIRNH study and 1.41 (0.79–2.41) in the MONICA study, the latter not reaching statistical significance due to lack of power. We may conclude from these figures that subjects with a parental history of premature fatal CHD have about 40% more ischemic ECG abnormalities. In the combined group of men aged 45 to 64, the odds ratio for ECG ischemia associated with a positive parental history was 1.30 (1.04–1.63), after additional adjustment for study.
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Table 6 Association Between Parental History of Premature CHD Death and CHD Risk Factors in the Offspring in the Three Studies
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Discussion
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A parental history of premature CHD is recognized as an important independent risk factor for early onset of cardiovascular risk factors and cardiac-related diseases. Several epidemiological studies (5–32) have dealt with familial aggregation of CHD in adult men and women. Some concentrated on the triggering role of a familial predisposition for CHD in the effect of lifestyle-related factors on the early onset of cardiovascular risk factors (10,22,23,26,32). The predictive value of familial clustering of CHD has been established in populations with high as well as low CHD incidence rates (26,28,31). Consequently, during the last decades, family history of CHD is given more attention as a major risk factor in preventive medicine and in guidelines for clinical practice (43). In most studies, the effect of parental history of premature CHD has been evaluated, mostly in cross-sectional settings, by comparing "cases" of a first-degree familial occurrence of fatal or nonfatal CHD with "controls," with respect to blood pressure, serum lipids and apolipoproteins and other classical risk factors for cardiac diseases.
Apart from the use of the ECG as a valid and reproducible diagnostic tool for heart disease, many reports in the epidemiological literature have dealt with the prognostic value of signs of ischemia on the resting ECG in apparently healthy subjects (1–4). Although more prevalent in women, ST-T changes are found to carry the same predictive risk in both sexes (4). Despite the importance in preventive cardiology of both ECG ischemia and a positive family history of CHD, we found no reports in the medical literature on the association between these two well-established risk factors. Hence, our objective was to investigate whether sons and daughters of subjects who died prematurely from CHD showed more ECG evidence of ischemia than persons with a negative parental history. We further assessed independence from classical risk factors for age, BMI, smoking, gender, blood pressure and serum cholesterol, using data from three large epidemiological studies carried out in Belgium in the past three decades.
Strength and specificity of the observed association.
The results are straightforward in the sense that the strength of the association was observed consistently in three separate databases, with an independent excess of about 40% in prevalence of ischemic ECG abnormalities in persons with a positive family history. As the association was independent of classical cardiovascular risk factors such as smoking, overweight, high blood pressure and high serum cholesterol, the effect of parental premature CHD on ECG ischemia is "superimposed" on these risk factors. In middle-aged men, the impact of a positive parental history of premature fatal CHD on the occurrence of ECG ischemia (odds ratio [OR] = 1.36) was moreover found to be stronger than the impact of family clustering on hypertension (OR = 1.24) or high cholesterol levels (OR = 1.10), associations extensively dealt with in the literature (18,25,26,28,44–53).
The observed association might be explained in part by clustering of lifestyle habits (54,55). However, the BIRNH database allowed us to adjust the observed association for smoking, polyunsaturated-to-saturated fat intake and alcohol consumption, known to be familial adopted behaviors. Analysis with and without adjustment for these background variables did not alter the strength of the association; the odds ratios in men and women combined remained 1.40 in both analyses. Some authors suggest that the familial aggregation of coronary heart disease is partly mediated by high-density lipoproteins (HDLs) (47). Since in the BIRNH survey and in the MONICA study HDL concentrations were determined, we were able to compare the HDL distributions between the groups with and without parental history of premature CHD death (results not shown). In both studies, no differences in HDL concentrations were found between groups. We also performed an extra analysis including HDL levels as a covariate in the multivariate model. In this analysis, again, the odds ratio remained 1.40, showing that the association is independent of HDL concentration.
Our definition of ECG ischemia included codes referring to signs of an old myocardial infarction, Minnesota Codes I1–3 (Q and QS patterns). Using a less stringent definition of ECG ischemia by excluding the subjects showing major Q wave findings on their resting ECG, the adjusted odds ratios for ECG ischemia (mainly ST-T codes), related to a positive parental history of premature CHD, were 1.39, 1.41 and 1.56 in the BHDPP, BIRNH and MONICA studies, respectively. Hence, premature CHD mortality is also related to unrecognized ischemia of the ST-T type in the offspring. In this report, we concentrated only on the offspring of parents who died prematurely. The offspring of persons having died not prematurely from CHD (father aged over 60; mother over 70) were not included in the "risk group" but rather in the ‘control’ group. Consequently, the intrinsic strength of the association between a positive parental history of fatal CHD, combining both premature and nonpremature cases, is likely to be more pronounced than the one reported here.
Bias considerations.
We considered the possibility of information bias. Our results could have been affected by "recall bias," as in any case-control study in which exposure is characterized from questionnaire data (56,57). Indeed, subjects suffering from heart disease may have a better recall of cardiac diseases in their parents. However, as the main outcome in our study is the prevalence of ischemic ECG findings, an indication of ischemia unknown to asymptomatic subjects, a differential recall bias is not likely to play an important role. One could argue that blood relatives or premature fatal CHD cases may have been advised to have themselves examined for cardiovascular diseases, so that the offspring are more likely to be aware of their risk factor profile and CHD status, including ECG abnormalities. This also may lead to an over-representation of subjects with a positive family history among "cases" of ECG ischemia. In the three studies, the proportions of records excluded due to insufficient data about parental vital status or cause of death were rather similar: 20% in the BHDPP study, 16% in the BIRNH study and 15% in the MONICA study. In an additional analysis (results not shown), we compared "cases" with ECG ischemia with "controls" without ECG ischemia in respect to missing information, after adjustment for age and sex. In none of the three databases was any difference detected in the proportion of insufficient information on the paternal history. Again, we conclude that information bias is not likely to distort the strength of the association with ischemic ECG findings observed in our study. Nondifferential misclassification bias in "exposure" (positive family history) as well as in the "disease" under study (ECG ischemia) is also unlikely to be an issue. Statistically, the "dilution" of case series with misclassified controls, and vice versa, introduces a bias towards the null hypothesis. In our study, the fact that subjects may indeed have been incorrectly classified in the ECG ischemia group due to measurement error or inaccurate reading of their ECG does not invalidate our findings. Rather, it implies that the strength of the observed association is underestimated.
Although the participation rates in the three studies were rather different, ranging from 36% in the BIRNH study to 71% in the BHDPP study, selection bias could have been important in the interpretation of our results. However, the consistency of the effect size observed in the three studies suggests that selection bias has no major influence on the reported associations.
Conclusions.
Cross-sectional data from three large epidemiological studies performed in Belgium during the past decades suggest that the offspring of parents having prematurely died from CHD have a great frequency and risk of ECG ischemia. The strength of this observed relationship was found to be very consistent in the three databases. These findings warrant further research into the genetics and possible pathogenic mechanism underlying familial aggregation of coronary heart disease.
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Footnotes
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This study was supported by a research grant from the Belgian National Fund for Scientific Research (Brussels, Belgium) (contract no. 3.9002.79).
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References
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