Anxiety, Depression and Risk of Acute Myocardial Infarction
Anxiety, Depression and Risk of Acute Myocardial Infarction
In this large population-based cohort study, participants with symptoms of anxiety, depression and mixed symptoms (MSAD) had a 20–30% increased risk for first AMI. Participants reporting two episodes of MSAD, 10 years apart, had >50% increased risk for AMI. All effects were robust to extensive adjustments for socioeconomic and traditional cardiovascular risk factors. For depression symptoms, the effect was only evident the first 5 years of follow-up, which raises a possibility for a reverse causation. For anxiety symptoms and MSAD, AMI risk attenuated with exclusion of participants with co-existent chronic physical illnesses at baseline, which probably reflects confounding.
Although anxiety and depression symptoms tend to overlap, these conditions have to date mostly been investigated separately in terms of risk for AMI. A recent meta-analysis of 23 prospective studies including a wide range of anxiety measures, found a pooled effect-size associated with incident cardiac heart disease of 1.26 (95% 1.15–1.38). Only 22% of the anxiety studies included in the meta-analysis consisted of both men and women. In our study, the relative risks for AMI in relation to anxiety and depression symptoms were similar in the two sexes and the overall effect was comparable to previous studies.
For depression, another meta-analysis including 21 prospective studies reported a pooled effect of 1.95 (95% CI 1.51–2.51) on CAD death and AMI, considerably higher than the point estimates found in our study. We can think of several explanations for this discrepancy; first, studies using self-report instruments have generally found smaller effects than studies relying on clinical diagnosis or psychiatric interviews. Second, adjustment for cardiovascular risk factors and comorbid physical illness(es) was limited in most previous studies. Third, large population-based studies tended to report lower point estimates than smaller studies probably due to publication bias. Finally, we shall emphasize that previous studies used diagnostic interviews or self report instruments that included a wide depressive symptom spectrum, such as sleep problems, lack of energy and disturbed appetite. These symptoms greatly overlap with symptoms of common physical illnesses, including subclinical coronary artery disease. As a result, the genuine contribution of core psychological and cognitive symptoms of anxiety and depression to cardiovascular morbidity has been uncertain. Importantly, the tool used in the current study, i.e. HADS, was originally designed for detection of anxiety and depression in patients with physical illness, and systematically excludes somatic symptoms which can mimic heart disease. Hence, our study is one of the first to link core psychological and cognitive symptoms of anxiety and depression to a moderately increased AMI risk. Nevertheless, by using this approach, some participants with predominantly somatic symptoms of depression might go undetected. As a consequence, we are likely to have underestimated, rather than overestimated, the association between depression and AMI in our study.
Most studies confirm that comorbid anxiety and depression are associated with more severe illness, worse outcome, and increased mortality compared with single conditions. This was not confirmed in our study, as we found no excess risk for AMI associated with MSAD in HUNT 2.
Limited previous evidence suggested that information on anxiety or depressive symptoms provided by repeated measures enable a considerably better risk prediction when compared with the information derived from a single measurement. Our study supports these earlier findings and suggests that persistent or recurrent symptoms might be associated with increased cardiovascular risk. One can hypothesize that a single measurement could reflect a normal reaction to stressful events, while multiple episodes may better capture anxiety and depressive disorders, such as bipolar disorders, known for poorer adherence with lifestyle and medical advice.
Our sensitivity analysis regarding depressive symptoms, but not anxiety or mixed symptoms, indicate a higher risk for AMI in the first 5 years of follow-up. This might reflect a reverse causation. The possibility that both depressive symptoms and subsequent AMI are caused by subclinical manifestations of atherosclerosis is among the greatest challenges for research on the prospective association between depression and AMI. Individuals free from clinical heart disease included in prospective studies may not be free from atherosclerosis, which is known to develop during decades before first symptoms. Thus, individuals free from clinical heart disease included in prospective studies may not be free from atherosclerosis. Atherosclerosis may facilitate depressive symptoms even before generating cardiac ischaemia creating a spurious association between depression and atherosclerosis. One possible pathway is the depressogenic actions of the increased inflammatory activity. Moreover, neuroimaging and neuropathology studies suggest that late onset depression often has a cerebrovascular origin. Cerebral atherosclerosis may thus facilitate depressive symptoms even before coronary atherosclerosis generates cardiac ischaemia.
Several epidemiological findings supported the reverse causality hypothesis. Studies with a shorter follow-up generally show stronger association with AMI. In the PRIME study, depressive symptoms were associated with coronary heart disease only in the first 5 years of follow-up, a finding which is confirmed in our study. There were some studies with null findings which were conducted in young populations, where vascular depression and subclinical CAD are less likely. In a study of healthy US army personnel 39–45 years of age, no correlation was found between depression and subclinical coronary artery disease identified by electron-beam computed tomography. Further, in a large prospective cohort study of men who were 19–21 years old at baseline, only anxiety but not depression was associated with future CAD risk.
While adjustment for established cardiovascular risk factors was extensive in several studies regarding anxiety, many prospective studies of depression and AMI risk failed to adjust even for well-known cardiovascular risk factors such as smoking and physical activity. Furthermore, comorbid physical disorders are among the most overlooked confounders in previous prospective studies of anxiety or depression and subsequent heart disease. Depressive symptoms are highly correlated with the overall disease burden, and several common chronic disorders are risk factors for AMI. In the present study, AMI risk in participants with symptoms of anxiety and MSAD at baseline was attenuated considerably after excluding all participants with comorbid chronic diseases from the analysis. In contrast, the excess AMI risk in those with depression symptoms and recurrent MSAD was more robust throughout these analyses.
Compared with prior studies, we had an ample statistical power to address the prospective association between symptoms of depression and anxiety, and the risk for AMI. The population-based nature of the study, the high stability (less than 0.3% net migration/year), and relatively high genetic and socioeconomic homogeneity of the population along with reliable hospital and register information covering the entire county, ensured close to complete follow-up and minimized the possibility for the misclassification of endpoints or for a selection bias. Moreover, in contrast to many previous studies, we could extensively control for potentially confounding factors.
Yet, the present work has some important limitations. Attendance in HUNT 2 was generally high, but considerably lower in the age group of 70 years and older. Further, we had no information on treatment for depression. SSRIs, the most commonly used medication for anxiety and depression, are known to reduce platelet adhesion and increase BMI and therefore are potential mediators for the observed associations. However, in the present study, it was not possible to separate the effect of depression and its eventual treatment.
Discussion
In this large population-based cohort study, participants with symptoms of anxiety, depression and mixed symptoms (MSAD) had a 20–30% increased risk for first AMI. Participants reporting two episodes of MSAD, 10 years apart, had >50% increased risk for AMI. All effects were robust to extensive adjustments for socioeconomic and traditional cardiovascular risk factors. For depression symptoms, the effect was only evident the first 5 years of follow-up, which raises a possibility for a reverse causation. For anxiety symptoms and MSAD, AMI risk attenuated with exclusion of participants with co-existent chronic physical illnesses at baseline, which probably reflects confounding.
Comparisons With Previous Studies
Although anxiety and depression symptoms tend to overlap, these conditions have to date mostly been investigated separately in terms of risk for AMI. A recent meta-analysis of 23 prospective studies including a wide range of anxiety measures, found a pooled effect-size associated with incident cardiac heart disease of 1.26 (95% 1.15–1.38). Only 22% of the anxiety studies included in the meta-analysis consisted of both men and women. In our study, the relative risks for AMI in relation to anxiety and depression symptoms were similar in the two sexes and the overall effect was comparable to previous studies.
For depression, another meta-analysis including 21 prospective studies reported a pooled effect of 1.95 (95% CI 1.51–2.51) on CAD death and AMI, considerably higher than the point estimates found in our study. We can think of several explanations for this discrepancy; first, studies using self-report instruments have generally found smaller effects than studies relying on clinical diagnosis or psychiatric interviews. Second, adjustment for cardiovascular risk factors and comorbid physical illness(es) was limited in most previous studies. Third, large population-based studies tended to report lower point estimates than smaller studies probably due to publication bias. Finally, we shall emphasize that previous studies used diagnostic interviews or self report instruments that included a wide depressive symptom spectrum, such as sleep problems, lack of energy and disturbed appetite. These symptoms greatly overlap with symptoms of common physical illnesses, including subclinical coronary artery disease. As a result, the genuine contribution of core psychological and cognitive symptoms of anxiety and depression to cardiovascular morbidity has been uncertain. Importantly, the tool used in the current study, i.e. HADS, was originally designed for detection of anxiety and depression in patients with physical illness, and systematically excludes somatic symptoms which can mimic heart disease. Hence, our study is one of the first to link core psychological and cognitive symptoms of anxiety and depression to a moderately increased AMI risk. Nevertheless, by using this approach, some participants with predominantly somatic symptoms of depression might go undetected. As a consequence, we are likely to have underestimated, rather than overestimated, the association between depression and AMI in our study.
Most studies confirm that comorbid anxiety and depression are associated with more severe illness, worse outcome, and increased mortality compared with single conditions. This was not confirmed in our study, as we found no excess risk for AMI associated with MSAD in HUNT 2.
Limited previous evidence suggested that information on anxiety or depressive symptoms provided by repeated measures enable a considerably better risk prediction when compared with the information derived from a single measurement. Our study supports these earlier findings and suggests that persistent or recurrent symptoms might be associated with increased cardiovascular risk. One can hypothesize that a single measurement could reflect a normal reaction to stressful events, while multiple episodes may better capture anxiety and depressive disorders, such as bipolar disorders, known for poorer adherence with lifestyle and medical advice.
Our sensitivity analysis regarding depressive symptoms, but not anxiety or mixed symptoms, indicate a higher risk for AMI in the first 5 years of follow-up. This might reflect a reverse causation. The possibility that both depressive symptoms and subsequent AMI are caused by subclinical manifestations of atherosclerosis is among the greatest challenges for research on the prospective association between depression and AMI. Individuals free from clinical heart disease included in prospective studies may not be free from atherosclerosis, which is known to develop during decades before first symptoms. Thus, individuals free from clinical heart disease included in prospective studies may not be free from atherosclerosis. Atherosclerosis may facilitate depressive symptoms even before generating cardiac ischaemia creating a spurious association between depression and atherosclerosis. One possible pathway is the depressogenic actions of the increased inflammatory activity. Moreover, neuroimaging and neuropathology studies suggest that late onset depression often has a cerebrovascular origin. Cerebral atherosclerosis may thus facilitate depressive symptoms even before coronary atherosclerosis generates cardiac ischaemia.
Several epidemiological findings supported the reverse causality hypothesis. Studies with a shorter follow-up generally show stronger association with AMI. In the PRIME study, depressive symptoms were associated with coronary heart disease only in the first 5 years of follow-up, a finding which is confirmed in our study. There were some studies with null findings which were conducted in young populations, where vascular depression and subclinical CAD are less likely. In a study of healthy US army personnel 39–45 years of age, no correlation was found between depression and subclinical coronary artery disease identified by electron-beam computed tomography. Further, in a large prospective cohort study of men who were 19–21 years old at baseline, only anxiety but not depression was associated with future CAD risk.
While adjustment for established cardiovascular risk factors was extensive in several studies regarding anxiety, many prospective studies of depression and AMI risk failed to adjust even for well-known cardiovascular risk factors such as smoking and physical activity. Furthermore, comorbid physical disorders are among the most overlooked confounders in previous prospective studies of anxiety or depression and subsequent heart disease. Depressive symptoms are highly correlated with the overall disease burden, and several common chronic disorders are risk factors for AMI. In the present study, AMI risk in participants with symptoms of anxiety and MSAD at baseline was attenuated considerably after excluding all participants with comorbid chronic diseases from the analysis. In contrast, the excess AMI risk in those with depression symptoms and recurrent MSAD was more robust throughout these analyses.
Strengths and Limitations
Compared with prior studies, we had an ample statistical power to address the prospective association between symptoms of depression and anxiety, and the risk for AMI. The population-based nature of the study, the high stability (less than 0.3% net migration/year), and relatively high genetic and socioeconomic homogeneity of the population along with reliable hospital and register information covering the entire county, ensured close to complete follow-up and minimized the possibility for the misclassification of endpoints or for a selection bias. Moreover, in contrast to many previous studies, we could extensively control for potentially confounding factors.
Yet, the present work has some important limitations. Attendance in HUNT 2 was generally high, but considerably lower in the age group of 70 years and older. Further, we had no information on treatment for depression. SSRIs, the most commonly used medication for anxiety and depression, are known to reduce platelet adhesion and increase BMI and therefore are potential mediators for the observed associations. However, in the present study, it was not possible to separate the effect of depression and its eventual treatment.
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