Considering plausible causal mechanisms via which optimistic biases might act to prevent heart disease is important; however, we must also thoroughly examine whether our prior observations of the CVD risk perception--outcome association are, in fact, confounded by unmeasured CVD risk factors. Risk perceptions are plausibly influenced by psychological conditions (i.e. personality, mood, coping style) that influence inflammatory status and endothelial reactivity. Since biomarkers of systemic inflammation (C-reactive protein) and endothelial dysregulation (Vascular Endothelial Growth Factor) also predict CVD events [11-16], these physiologic processes represent important pathways for potential confounding of the risk perception--CVD outcome association (see conceptual diagram in Figure ​Figure1).1). We hypothesize that controlling for markers of systemic inflammation and endothelial dysregulation will weaken earlier observations of a strong protective association between optimistic ratings of CVD risk and 15-year CVD mortality among community-dwelling men [9].

The association between comparative optimism and a lower probability of CVD death was strong (OR = 0.39, 95% CI = 0.17, 0.91). Adjusting for CRP alone, VEGF alone, or in combination with age, income and Framingham Risk Score did not substantially change these findings [see Table ​Table2].2]. Similar results were observed for biomarker classification as a continuous (log-transformed) or categorical (tertile) variable.

Psychosocial and behavioral processes related to self-enhancement and optimism might explain our findings. Believing that one is invulnerable from future problems may enhance motivation to pursue other activities that, in turn, buffer the effect of stress on CVD risk. In addition, people who perceive lower risk may also plan to take measures to reduce risk, making their perceptions accurate.

Another possible explanation is that optimistic ratings of CVD risk reflect an optimistic personality. Optimists seem to experience better health than non-optimists. Among cardiac patients, optimists show faster recovery from cardiac bypass surgery [19] and are less likely to be hospitalized 6 months post-surgery [20]. The beneficial health effects of optimism may arise from the different ways that optimists and pessimists cope with stress. Optimism is correlated with active and problem-focused coping strategies [21] that may lead to better health practices. Research has found that optimists do seem to be more effective in changing their own health behaviors and they report engaging in more healthy behaviors than do pessimists [22]. For example, when compared with pessimistic patients, optimistic cardiac patients were more successful in lowering their fat intake and getting more exercise [23]. However, prior work observes that the correlation between optimistic risk perceptions and global optimism is weak, ranging from r = 0.14 to r = 0.33 [24], thus suggesting that optimistic appraisal of one's CVD risk represents a sub-domain of optimism with potentially important cardio-protective implications.

Fiscella [25] raises important questions about whether optimistic ratings of health status--well known to predict survival [26]-- confound the cardio-protective association with optimistic self-ratings of CVD risk observed in this cohort. Health status was not measured, thus precluding us from directly addressing confounding (or interaction between optimistic ratings of health status and risk). However, optimistic self-rated health is associated with lower levels of systemic inflammation [27,28]. We observed no such relationship between optimistic ratings of CVD risk and systemic inflammation. Furthermore, controlling for systemic inflammation failed to weaken the observed cardio-protective effects of optimistic ratings of CVD risk. Thus, we conclude that unmeasured confounding by self-rated health status is unlikely to threaten the validity of the strong relationship observed in the present study.

Our findings do not rule out the possibility for systemic inflammation or endothelial dysregulation to represent a partial causal mechanism linking risk perceptions to CVD mortality. For example, if heightened awareness of CVD risk leads to fear-related behaviors and physiological responses that promote systemic inflammation or endothelial reactivity, downstream effects on CRP levels might be observed. We measured CRP and VEGF at baseline only. Although this provides strong evidence that these biomarker-related phenomena do not confound the association between comparative optimism and CVD mortality, longitudinal assessment is necessary to determine the degree to which changes in systemic inflammation or endothelial dysregulation represents a causal pathway linking CVD risk perceptions and CVD death.