Body Weight in Early and Mid-Adulthood in Relation to Subsequent Coronary Heart Disease Mortality: 80-Year Follow-up in the Harvard Alumni Study FREE

In the very few studies conducted,^1- 4 obesity in young adults is generally associated with an increased risk of future coronary heart disease (CHD). However, data interpretation is complicated by methodological limitations, which include small study size; a paucity of studies examining the impact of confounding factors; and unexplored mechanisms, including the essentially unknown contributions of early vs later body weight on CHD risk,^5- 6 which has implications for weight control interventions. In the largest and best characterized study to date, to our knowledge, we directly address these shortcoming.

The Harvard Alumni Health Study is a cohort study of men who had a routine medical examination as undergraduates at Harvard University, Cambridge, Massachusetts, between 1916 and 1950.⁷ Measurements of height, weight, and blood pressure were made, and students responded to enquiries regarding smoking habits⁷; details on physical activity were ascertained from university records.⁶ Questionnaires mailed to surviving alumni in either 1962 or 1966 included questions about height, weight, lifestyle habits, and medical history; a high level of agreement has been shown between these responses and direct measurements.⁷ Harvard Alumni Office listings were used to identify decedents, and copies of official death certificates were obtained with 99% coverage.⁸ Deaths from CHD were coded according to the seventh revision of the International Classification of Disease (ICD) (code 420).

Subjects in the present analyses had complete data on height and weight at both the university medical examination and the follow-up questionnaire (n = 18 995; Table). Cox regression was used to model the relation of early and later adult body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) with subsequent CHD mortality, with sequential adjustment for age, early adult CHD risk factors, midlife CHD risk factors, and midlife/early adult BMI (Table). Because midlife BMI is conceivably on the causal pathway of early adult BMI and mortality, we also used joint modeling to estimate these interrelationships.

A maximum of 82.5 years of follow-up (median, 56.4 years) gave rise to 2025 CHD deaths in the 18 995 men. The correlation between BMI in early adulthood and middle age was moderate (r = 0.49; P < .001). Men who were obese in early adulthood had nearly twice the risk of future CHD mortality (hazard ratio [HR], 1.83; 95% CI, 1.21-2.76), and there was evidence of a linear trend across BMI categories (P value for trend, .006) (age-adjusted analyses, Table). Adjustment for other confounding variables at college entry and potential mediating factors in middle age had little impact. However, when midlife BMI was added to the multivariable model, the predictive capacity of early BMI for later CHD mortality was greatly attenuated (HR, 1.21; 95% CI, 0.73-2.02). Early adult BMI was not significantly related to CHD (P = .42) in the joint model.

Body mass index in middle age was also associated with CHD mortality (P value for trend, <.001) such that study members who were overweight and obese experienced a 25% and 60% increased risk, respectively (age-adjusted analyses,Table). This association persisted following adjustment for all covariates (models 2 to 5). Similar results were obtained when we categorized BMI according to quartiles and when total mortality was the outcome of interest.

When we repeated our analyses with multiple imputation (n = 19 821) and also when we restricted analysis to the subset of men with no missing data on BMI and potential confounders (n = 14 638), the results were essentially unchanged (results not shown). We found similar associations between BMI during college and all-cause mortality (for obesity: HR, 1.46; 95% CI, 1.16-1.83), which remained significant after full adjustment (HR, 1.38; 95% CI, 1.06-1.81) (eTable). Stroke mortality was unrelated to BMI during college (HR, 0.39; 95% CI, 0.05-2.83).

In this cohort study we found a doubling in CHD mortality risk in men who were obese in early adulthood. This association held after adjustment for both confounding variables in early adulthood and potentially mediating factors in middle age but, importantly, was eliminated after taking in account midlife BMI.

Our findings contrast with the only other study with prospectively measured BMI in both early and later life, which found that elevated body weight in adolescence exerted an effect on CHD after adjusting for adiposity in midlife.⁴ In that study, there were considerably fewer deaths and therefore lower statistical power. In another prospective study, being overweight in college was associated with increased risk of future cardiovascular disease mortality, but no adjustment was made for subsequent BMI.³

While the Harvard Alumni Health Study has several advantages—its sample size and number of end points, a range of collateral data, and repeated BMI measurements—it is not without its shortcomings. While there is growing evidence to suggest that body composition (eg, central adiposity) in middle and older age is associated with CHD, the only measurement of adiposity available to us was BMI. Furthermore, the present analyses are restricted to men; it is plausible, although perhaps unlikely, that different results may have been seen in women.

In conclusion, the apparent doubling of future CHD risk in men who were obese in early adulthood was effectively eliminated following control for BMI in middle age. These results require replication in other studies.