We found that depressive symptoms were associated with elevated levels of norepinephrine excretion in 598 subjects with coronary heart disease. The participants with depressive symptoms were more likely than those without to have increased levels of 24-hour mean norepinephrine excretion, to have norepinephrine excretion levels in the highest quartile, and to have norepinephrine excretion levels above the normal range. The presence of depressive symptoms was not associated with 24-hour urinary epinephrine or dopamine levels.
Because a high norepinephrine level is an established risk factor for cardiac events and mortality (17
), our findings suggest that elevated norepinephrine may contribute to the increased risk of cardiac events associated with depressive symptoms (7
). It is well known that norepinephrine is increased in patients with heart failure, correlates with the severity of heart failure, and is associated with increased mortality in cardiac patients (28
). In our sample, a high level of norepinephrine excretion was associated with the lower left ventricular ejection fraction. These adverse effects of norepinephrine levels have been shown not only in patients with heart failure (21
) but also in population-based samples of apparently healthy elderly subjects (20
), in asymptomatic patients without clinically relevant heart failure (18
), in patients with end-stage renal disease without heart failure (19
), and in patients with tachyarrhythmias without heart failure (17
). These findings argue for a more causative role of norepinephrine in increasing the risk for cardiac events and mortality. Possible mechanisms include direct toxic effects of norepinephrine on cardiocytes (16
), its ability to trigger tachyarrhythmia (17
), and its role in the promotion of platelet aggregation and platelet thrombi formation (18
To our knowledge, only one previous study has examined the association between depressive symptoms and norepinephrine levels in patients with coronary heart disease (13
). Carney et al. (13
) measured plasma norepinephrine levels in 50 depressed and 39 nondepressed subjects with coronary heart disease but did not find an association between depressive symptoms and plasma norepinephrine levels. Unlike our study, their measurement of norepinephrine was based on a series of plasma norepinephrine levels at baseline and at three time points within 10 minutes after orthostatic challenge. It is possible that integrated 24-hour urinary measurement of norepinephrine is a more sensitive measure for the detection of differences in norepinephrine levels.
The causal direction between depressive symptoms and norepinephrine levels cannot be determined by our cross-sectional study. However, a plausible mechanism linking depressive symptoms with increased sympathetic activity is the enhanced activity of hypothalamic and extrahypothalamic corticotropin-releasing factor (CRF) in depressed patients. It is well established that CRF is increased in medically healthy patients with depressive symptoms (10
), leading to increased cortisol levels (33
). Moreover, a large body of evidence suggests that both hypothalamic and extrahypothalamic CRF activate the locus ceruleus in the brain, leading to an increase in norepinephrine (36
Accordingly, earlier studies have found that depressed patients who were cortisol nonsuppressors after receiving dexamethasone had higher norepinephrine levels. Moreover, administration of a CRF antagonist led to a diminished norepinephrine response to stress in primates (40
). Thus, high CRF activity may simultaneously lead to elevated cortisol and norepinephrine levels (41
). Moreover, levels of CSF norepinephrine and plasma cortisol were increased and highly correlated in depressed patients, which is also consistent with the increased CRF activity causing these alterations (11
). In turn, norepinephrine enhances forebrain CRF activity, possibly closing a feed-forward loop leading to higher activity of both norepinephrine and CRF in depressed patients (37
). Indeed, in this study group, we also found increased cortisol levels in depressed patients (42
), consistent with this model of norepinephrine-CRF interaction (10
We did not find an association between depressive symptoms and epinephrine or dopamine levels in this group, which is in accordance with an earlier study that also found increased norepinephrine but similar epinephrine levels in depressed patients (12
). This might suggest that depressive symptoms are more closely related to increased sympathetic nervous system activity, as reflected in increased norepinephrine levels compared with the adrenomedullary system and reflected levels of epinephrine excretion. Indeed, it has been shown that there is a differential response of the sympathetic nervous and adrenomedullary hormonal systems, depending on the type and severity of a stressor (43
Several limitations should be considered in interpreting the results of our study. Only 58% (598 of 1,024) of the Heart and Soul Study participants were included in this analysis. However, the prevalence of depressive symptoms was similar in the participants who were included or excluded from the analysis. Although we made every effort to systematically assess medication use and to ensure complete urine collection, our results were limited by self-reported medication use and compliance with the urine collection procedure. Only 17% of our participants were women, thereby reducing our power to detect interactions by gender and limiting the generalizability of our results. Finally, most of the catecholamine values in our group were within the normal range, and their clinical significance is unclear. However, the Heart and Soul Study is an ongoing prospective study that will follow patients to determine whether greater norepinephrine levels at baseline contribute to the association of depressive symptoms with worse outcomes in patients with coronary heart disease.
In summary, we found that depressive symptoms are associated with elevated levels of norepinephrine excretion but not with epinephrine or dopamine excretion levels in medical outpatients with heart disease. Increased levels of norepinephrine excretion may contribute to an increased risk of future cardiac events in patients with depressive symptoms.