European Heart Journal Advance Access originally published online on March 11, 2008
European Heart Journal 2008 29(7):835-836; doi:10.1093/eurheartj/ehn074
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Why do men and women differ in their risk of myocardial infarction?
St Vincent's Institute of Medical Research and the Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Victoria, Australia
* Corresponding author. Tel: +61 3 9288 2480, Fax: +61 3 9416 2676, Email: dcampbell{at}svi.edu.au
This editorial refers to ‘Risk factors for myocardial infarction in women and men: insights from the INTERHEART study’
by S.S. Anandet al.,on page 932
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
Cardiovascular disease is a global problem. To enable more effective prevention strategies for myocardial infarction (MI), the INTERHEART study looked for differences between countries, and between men and women, in risk factors for acute MI.1 It was a case–control study with 15 152 cases of acute MI and 14 820 controls from 262 centres from 52 countries. Information about nine risk factors was collected: smoking, self-reported hypertension and diabetes, measured waist/hip ratio, psychosocial factors, diet, physical activity, alcohol consumption, and measured apolipoprotein B/apolipoprotein A1 ratio.1 In their first report. the INTERHEART Investigators concluded that these nine risk factors accounted for most of the risk for acute MI in both sexes, at all ages, and in all regions.1 When all nine risk factors were included in the analysis, the population-attributable risk for men 
55 years was 93.1% and for women 65 years was 96.5%, indicating that most premature MI is preventable.1
The INTERHEART Investigators have now extended their analysis of risk factors for MI in men and women.2 They addressed the specific question of why women have their first MI 9–10 years after men by examining whether differences exist between women and men in risk factor distribution across various age categories. The 12 460 cases were 18% fewer than the number in the initail report, and the 14 634 controls were similar in number to those in the initial report. There were some differences in definition of risk factors compared with the initial report and, rather than the different age cut-off points for younger and older men and women in their initial study,1 they used the same age cut-off point of 60 years for both men and women. As shown by the initial analysis,1 women experienced their first acute MI on average 9 years after men, and the age difference was similar across all regions. The nine risk factors explained 96 and 93% of the population-attributable risk for women and men, respectively.2 Anand et al. examined the contribution of risk factors to the 9-year delay in first MI in women by calculating how much the nine risk factors explained the probability of MI before the age of 60. Before adjustment for the nine risk factors, the probability of an acute MI occurring before the age of 60 was 60.6% for men and 33.0% for women, a difference of 27.6%. Using a case-only approach, a prediction model that included all nine risk factors and region explained 93.3% of acute MI in men <60 years and 88.6% of acute MI in women <60 years, a difference of 4.7%. Given that adjustment for these risk factors reduced by >80% the sex difference in probability of MI occurring before age 60, Anand et al. concluded that men had their first MI at a younger age than women because younger men had higher risk factor levels than younger women.2
Which risk factors were responsible for men having their first MI at a younger age? Comparison of the prevalence of risk factors in younger men and women showed that the main contributors were the higher prevalence of lipid abnormalities and smoking in younger men, although they did appear to obtain some protection from their higher alcohol consumption. On face value, these data suggest that if younger men reduced their smoking and lipid abnormalities to the levels seen in younger women, they would live 9–10 years longer before their first MI. There is some support for this conclusion.3 Many different mechanisms for the lower MI risk of women have been proposed.4,5 Anand et al. suggest that the failure of risk factors to explain the difference in MI risk between men and women in previous studies5,6 was because previous studies did not include all of the risk factors measured by the INTERHEART study, particularly apolipoproteins and abdominal obesity, and also diet, physical activity, and psychosocial factors. Larsson et al. reported that differences in body fat distribution explained most of the difference in MI risk between men and women.7 However, the INTERHEART study found no difference in abdominal obesity between men and women, which reflected the inclusion of subjects not only from typical Western countries where abdominal obesity was more common in men, but also from the Middle East, South Asia, and South America, where abdominal obesity was more frequent in women. Thus, while abdominal obesity was a risk factor for first MI, its contribution to the younger age of men at first MI applies only to countries where abdominal obesity is more common in men than in women.
By design, the INTERHEART study recruited subjects with acute MI who survived to hospitalization and had a recognized MI. Important to the debate about whether risk factors explain the difference in MI risk between men and women are the possible differences in the proportions of men and women who die before hospitalization, or who have otherwise unrecognized MI. More than 30% of subjects with acute MI do not survive to hospitalization, and women may be more likely to die before hospitalization than men.8 Moreover, the Rotterdam study found that the proportion of unrecognized MI in women (54%) was higher than in men (33%).9 The Framingham study also reported a higher proportion of unrecognized MI in women,10 whereas the ARIC study reported similar proportions for unrecognized MI in men and women.11 Women may be more likely to have an unrecognized MI because they are less likely than men to report chest pain or discomfort when they present with an acute coronary syndrome.12 A higher proportion of women with acute MI who die before hospitalization, or who have otherwise unrecognized MI, might explain part of the difference in MI risk between men and women. While the failure to account for deaths before hospitalization and otherwise unrecognized MI may have biased the assessment of demographics and risk factors in the INTERHEART study, it probably did not influence the conclusions.
Where does this leave sex (and oestrogen) as a determinant of MI risk? Oestrogens were once considered to provide protection from atherosclerosis, but randomized studies of hormone replacement therapy caused a reassessment of the relationship between oestrogen and MI risk.13 The INTERHEART study showed important differences between men and women in the impact of risk factors on MI risk. Although current smoking carried a similar risk in men and women, former smoking carried more risk in men. Hypertension, diabetes, psychosocial factors, lack of physical activity, and lack of alcohol consumption were more potent risk factors for acute MI in women than in men. In their original report, the INTERHEART Investigators suggested this was because women with acute MI were in general 10 years older than men with acute MI. However, the analysis by Anand et al. indicates that this explanation may not be correct. When women aged <60 were compared with women aged 
60 years, younger women had a higher risk from abnormal lipids, smoking, hypertension, and diabetes than older women. Thus, there was no evidence that more recent exposure to oestrogens in the younger women provided any protection from these risk factors.
What does this study mean for prevention? Both men and women have much to gain from prevention strategies, men more so than women, and there may be a place for a difference in emphasis between strategies for men and women. For men, the emphasis should be on smoking cessation and improvement in lipid abnormalities, but other risk factors should not be neglected. For women, hypertension and diabetes may need to be treated more aggressively. There should be greater attention to increased physical activity as a strategy to prevent diabetes. With regard to alcohol consumption, Yusuf et al. have argued that any attempt to encourage alcohol consumption may produce more harm than benefit.1
In conclusion, this analysis by Anand et al. of the INTERHEART data reinforces the conclusions of the main study, which were that potentially modifiable risk factors account for most of the MI risk in both men and women at all ages and in all regions. Risk factors appear to account for most of the difference in MI risk between men and women. The challenge is to apply these findings to more effective prevention strategies.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehn018 
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Related articles in EHJ:
- Risk factors for myocardial infarction in women and men: insights from the INTERHEART study
- Sonia S. Anand, Shofiqul Islam, Annika Rosengren, Maria Grazia Franzosi, Krisela Steyn, Afzal Hussein Yusufali, Matyas Keltai, Rafael Diaz, Sumathy Rangarajan, Salim Yusuf, and on behalf of the INTERHEART Investigators
EHJ 2008 29: 932-940.[Abstract] [FREE Full Text]
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