Relationship Between Hemoglobin Concentration and Cardiovascular Disease Mortality in a 25-Year Follow-up Study of a Japanese General Population ― NIPPON DATA90 ―

Background: Deviations of hemoglobin from normal levels may be a factor in cardiovascular disease (CVD) risk; however, conclusive evidence is lacking. In addition, preclinical conditions may influence hemoglobin concentrations, but studies focusing on reverse causation are limited. Thus, we examined the relationship between hemoglobin concentrations and CVD mortality risk, considering reverse causation. Methods and Results: In a prospective cohort representative of the general Japanese population (1990-2015), we studied 7,217 individuals (mean age 52.3 years; 4,219 women) without clinical CVD at baseline. Participants were categorized into sex -specific hemoglobin quintiles (Q1-Q5) and data were analyzed using the Cox proportional hazards model adjusted for possible confounders. During a 25 -year follow-up, 272 men and 334 women died from CVD. Adjusted hazard ratios for CVD mortality across sex -specific quintiles, using Q3 as the reference, were significantly higher for Q1 (1.40; 95% confidence interval [CI] 1.08-1.82) and Q5 (1.49; 95% CI 1.14-1.96), and remained significant after excluding deaths within the first 5 years of follow-up to consider reverse causation (1.35 [95% CI 1.02-1.79] and 1.45 [95% CI 1.09-1.94], respectively). A similar U-shaped association was seen between transferrin saturation levels and CVD mortality, but after excluding deaths within the first 5 years the association was significant only for Q1. Conclusions: Low and high hemoglobin concentrations were associated with an increased risk of CVD mortality.