We found no evidence of an association between depression and low HRV in 873 outpatients with stable CHD. Overall, we observed no difference in time domain or frequency domain measures of HRV in participants with and without depression. Moreover, there was no correlation between continuous measures of depression severity and measures of HRV nor was there any association between severe depressive symptoms and HRV. These findings raise questions about whether HRV is a mediator in the association of depression with adverse outcomes among patients with stable CHD.
In patients with CHD, depression is associated with an almost 2-fold increased risk of CHD events and mortality,1-10
but no study has determined how depression leads to adverse outcomes. Several recent studies have suggested that autonomic dysfunction, represented by low HRV, may be one of the more promising potential explanations. Depression has been associated with low HRV in the setting of acute MI,12,17
and low HRV is associated with increased mortality following MI.13,15,16
In the ENRICHD study, Carney et al12
found a strong association between depression and low HRV (frequency domain variables) in 307 patients with depression compared with 366 patients without depression following acute MI. Furthermore, a number of small studies have reported improvements in HRV after treatment for depression,31,32
including 2 studies in patients with CHD.33,34
However, stable and unstable CHD have different pathophysiologic features, and it is thus possible that low HRV may act as a mediator between depression and adverse outcomes in patients with unstable but not stable CHD.
Our results differ from those of several small studies that have examined the association between depression and HRV in patients with stable CHD. Carney et al,21
in a study of 77 patients undergoing elective coronary angiography, found only a trend toward lower HRV in stable CHD. In another study, Carney et al22
reported lower HRV in 19 patients with depression compared with 19 patients without depression who were undergoing elective coronary angiography. Krittayaphong et al23
found an association between low HRV and higher depression scores in 42 patients with exercise-induced ischemia. Stein et al24
found lower HRV in 40 patients with depression compared with 32 patients without depression with documented CHD by angiography recruited from cardiac rehabilitation centers and newspaper advertisements. Conversely, Yeragani et al35
found no difference in HRV between 19 patients with depression and 20 control patients.
There are several possible explanations for the difference between our results and those of prior studies. First, recent trends in therapy for patients with CHD may eliminate the previously reported association between depression and HRV. However, we observed no evidence of an interaction between depression and β-blockers in our analysis and no association of depression with HRV in the subset of participants who were not taking β-blockers. Second, antidepressant medications, which have been shown to improve HRV post-MI, may blunt the effect of depression on HRV.34
However, the majority of patients with depression in our study were not taking antidepressants, and even after excluding those taking antidepressants, we still found no association between depression and HRV.
Third, 79 (9%) of our study participants had a diagnosis of PTSD within the past year, and comorbid PTSD may confound the association between depression and HRV. However, with the exception of an association between PTSD and low-frequency power, neither generalized anxiety disorder nor PTSD was associated with any HRV indexes in our analysis. Finally, we determined the presence of depression in the past month, and it is possible that the effect of depression may have been attenuated if the participant was not actually depressed during the same 24 hours as the HRV measurement. However, even when we limited our analysis to those who reported severe depressive symptoms in the prior 2 weeks, we observed no association between depression and HRV.
Another potential explanation is that participants with depression were healthier than participants without depression in our study or that the CDIS-IV misclassified some participants without depression as having depression, thus diluting the effect of depression on HRV. However, even after adjusting for the presence of medical illness, we observed no association between depression and HRV. Furthermore, after excluding the “healthier” subset of participants (ie, those who did not have a history of MI or revascularization), there was still no association between depression and HRV.
Several limitations must be considered in interpreting our results. First, only 161 (18%) of our participants were women, so our results may not generalize to other patient populations. However, our subset of women was larger than the total combined number of women enrolled in all previously published studies of depression and HRV in patients with stable CHD, and the total number of participants in our study was also greater than 3 times the total combined number of participants in these previously published studies. Second, we changed our HRV analysis software halfway through the study, so half of the Holter tapes were run using different software. However, in a blinded repeat analysis of 20 tapes, we found more than 99% concordance in readings between the 2 software programs. Finally, we did not use nonlinear techniques to measure HRV in our participants, and nonlinear techniques may be more sensitive to depression than those used in our study.36
In summary, we found no evidence that depression is associated with low HRV in a study of 873 patients with stable CHD. These findings raise questions about whether low HRV mediates the association between depression and adverse cardiovascular events.