In this nationwide population-based study, we found an association between the BMI in late adolescence and subsequent cardiovascular mortality, predominantly in midlife, since the cohort did not include participants who had reached the older ages at which cardiovascular disease is a dominant cause of death. BMI, including measurements in the currently accepted mid-normal range, was associated with a graded increase in the risk of death from cardiovascular causes. Obesity during adolescence was associated with a substantially increased risk of cardiovascular outcomes in middle age, particularly death from coronary heart disease. The associations, which were similarly evident in both sexes, persisted strongly for cardiovascular deaths occurring during four decades after the measurement of BMI in adolescence. The association withstood a series of sensitivity analyses. The population-attributable fractions in our study are projected to rise with the secular shift in the BMI distribution and indicate that overweight and obesity in adolescence may account for a fifth of cardiovascular deaths and a quarter of deaths from coronary heart disease by the time the participants reach midlife. Modeled predictions for the United States point to a marked increase in the incidence of coronary heart disease and in the rate of death in young and middle adulthood.15

Several studies2-4,11,16 (although not all6) have shown an association between obesity during adolescence and a future risk of death from coronary heart disease, with conflicting evidence regarding death from cerebrovascular causes.5,6 In the study by Baker et al.,2 in which investigators evaluated the association between childhood BMI and coronary events in adulthood, the BMI at the age of 7 years was associated with adult mortality from coronary heart disease (hazard ratio, 1.10 per 1-unit increment in the z score in boys); the strength of the association increased up to the age of 13 years (hazard ratio, 1.24). In our study, in similar analyses restricted to adolescents who were 17 or 18 years of age, we estimated hazard ratios for death from coronary heart disease of 1.54 and 1.58 for boys and girls, respectively, findings that appear to be consistent with a stronger association in adolescence than earlier in childhood.

The large size of our study, which incorporated more than 42 million person-years of follow-up, provided adequate statistical power to assess the associations within the currently accepted normal range of BMI values. Excess all-cause mortality (including cardiovascular mortality) starting at the 50th percentile of adolescent BMI values confirmed the findings of an earlier study on a portion of this cohort.17 Thus, the classification of BMI according to the accepted normal range (i.e., the 5th to 84th percentiles and a BMI ranging from 18.5 to 25.0) may underestimate the risk associated with being overweight in adolescence. This inference is supported by our findings that there is a graded increase in the risk of death starting at the mid-normal range of adolescent BMI (50th to 74th percentiles) and that the high-normal BMI range (75th to 84th percentiles) was associated with hazard ratios of 2.2 for coronary heart disease and 1.8 for total cardiovascular causes.

Our findings appear to provide a link between the secular trends in adolescent overweight and coronary mortality during the past decades. In contrast to the steep decline in the rate of death from cardiovascular causes among older age groups, cardiovascular mortality among young adults has not decreased or the decline has slowed in several developed countries.9,10

How might adolescent BMI affect adult cardiovascular mortality? In our study, we could not control for important risk factors (e.g., smoking, exercise, and physical fitness)18 or for adult BMI. We have considered two pathways by which adolescent BMI might influence cardiovascular outcomes in adulthood. First, obesity may be deleterious during adolescence, since it has been associated with unfavorable metabolic abnormalities (suggesting an indirect pathway mediated through risk factors such as unfavorable plasma lipid or lipoprotein levels, increased blood pressure, impaired glucose metabolism, and insulin resistance15,19), cardiac remodeling,20 lengthening of the QT interval,21 and formation of coronary and aortic atherosclerotic plaques.22 Furthermore, a mendelian randomization study showed a strong association between BMI and several cardiometabolic risk markers in the young (even within the nonobese weight range), which effectively ruled out uncontrolled confounding and reverse causation as explanations for their findings.23 Increased coronary risk associated with adolescent obesity persisted in a subgroup in our cohort,24 even after adjustment for BMI in young adulthood, which suggests the importance of the timing of exposure to obesity during a lifetime.12,25 However, other studies26,27 have not shown an independent association between BMI during adolescence and adult cardiovascular disease after adjustment for adult BMI. Second, as BMI tracks over time25,26 (and more strongly starting at the age of 18 years28), adult BMI may mediate the risk association. The association between adult BMI and cardiovascular disease is supported by a mendelian randomization study.29 Such a pathway might explain the association between seemingly normal levels of BMI (50th to 74th percentiles) and death from total cardiovascular causes and between a BMI of more than 20.0 and death from coronary artery disease. In the absence of adult measures of BMI, we were unable to address this question.

Our study has certain limitations. First, as noted, in the absence of adult measures of BMI, we could not assess an independent effect of adolescent BMI on death from cardiovascular disease in adulthood. Second, cause-specific data were unavailable to us for 6.8% of all deaths. However, simulations indicated only minor effects of missing data on our risk estimates. Third, we were unable to account for important cardiovascular lifestyle risk factors that may confound the BMI association, although adjustment for smoking had no effect in other studies,3,25 and a mendelian randomization study showed effects for BMI that were independent of confounding.23 Fourth, since our follow-up included participants in early and mid-adulthood but not in the older age groups in which cardiovascular death predominates, fewer than 10% of our study participants died from cardiovascular causes. Fifth, although the study sample was highly representative of the Israeli adolescent male Jewish population, it was less representative of Israeli women, and our findings need to be confirmed in a racially and ethnically diverse population. Finally, since we were analyzing only death outcomes, we cannot determine whether BMI was associated with the incidence of cardiovascular disease, death from cardiovascular disease, or both. The strengths of the study include the use of standardized measurements of weight and height rather than recalled values,30 the large sample size, and the extended follow-up, which provided adequate power to examine narrow subgroups of BMI percentiles.

In conclusion, an increased BMI in late adolescence, even within the currently accepted normal range, was strongly associated with cardiovascular mortality in young adulthood or midlife. We could not determine whether an increased BMI in adolescence is an independent risk factor, is mediated by adult obesity, or both. The secular shift to the right in the distribution of adolescent BMI and the rising prevalence of overweight and obesity among adolescents may account for a substantial and increasing future burden of cardiovascular disease, particularly coronary heart disease.