Author + information
- Ibhar Al Mheid, MD,
- Elizabeth Held, MD,
- Irina Uphoff, BS,
- Greg S. Martin, MD,
- Sandra Dunbar, PhD,
- Aurelian Bidulescu, MD,
- Gary Gibbons, PhD,
- Dean P. Jones, PhD,
- Viola Vaccarino, MD, PhD and
- Arshed A. Quyyumi, MD∗ ()
- ↵∗Emory Clinical Cardiovascular Research Institute, Emory-Georgia Tech Predictive Health Institute, Emory University Hospital, 1462 Clifton Road Northeast, Suite 507, Atlanta, Georgia 30322
Psychological stress triggers a cascade of physiologic responses including activation of the hypothalamic-pituitary axis and increase in adrenocorticotropic hormones. This contributes to an imbalance between the sympathetic and parasympathetic nervous systems, and can stimulate oxidant stress and inflammatory signaling that may accelerate metabolic and vascular dysfunction leading to atherosclerosis. As many as 20% of subjects hospitalized with a myocardial infarction report depressive symptoms, and patients with cardiovascular disease (CVD) have a 3-fold increased risk of developing depression compared with the general population. A higher burden of depressive symptoms is also associated with worse cardiovascular and noncardiovascular outcomes. However, the mechanisms by which depressive symptoms confer higher CVD risk remain to be fully elucidated.
Even asymptomatic individuals with increased arterial stiffness and oxidative stress are at a higher risk for development of CVD, and these measures are predictive of adverse long-term outlook in patients with established disease. Lower levels of plasma glutathione, an aminothiol that acts as the major intracellular antioxidant, are associated with presence of CVD and its major risk factors, and are a contributor to vascular dysfunction in healthy adults. In addition, both arterial stiffness and oxidative stress are amenable to improvement with effective pharmacologic and nonpharmacologic therapy, and can therefore serve as meaningful surrogates. It is unknown whether depressive symptoms correlate with increased arterial stiffness or systemic oxidant burden in healthy adults, or whether regular exercise may impact these relationships.
We examined the relationship between depressive symptoms and subclinical vascular disease, and evaluated the effects of regular physical activity in 965 subjects free of heart disease, cerebrovascular, or peripheral arterial disease, and without a prior diagnosis of an affective, psychotic, and/or anxiety disorder.
Subjects completed the Beck Depression Inventory-II (BDI-II) questionnaire that assesses depressive symptoms over the preceding 2 weeks using a 21-item questionnaire that addresses both affective (e.g., anhedonia) and somatic (e.g., dyssomnia) manifestations of depression. A score of 0 indicates absence of depressive symptoms and scores of 1 to 13, 14 to 19, 20 to 28, and 29 to 63 denote minimal, mild, moderate, and severe depression, respectively. Selected items from the Cross-Cultural Activity Participation Typical Week Physical Activity Survey were used to determine if subjects met the 2008 Physical Activity Guideline for Americans, which recommends 150 or 75 min/week of moderate- or vigorous-intensity physical activity, respectively, or an equivalent combination of the 2.
Oxidative stress was measured as plasma total glutathione, whereby higher oxidative stress is indicated by depleted levels of glutathione. Vascular function was assessed by applantation tonometry (Atcor, West Ryde, Australia), which included measurement of the augmentation index (AIX), a composite indicator of wave reflections calculated as the augmented pressure due to wave reflections divided by the aortic pulse pressure, as well as the subendocardial viability ratio (SEVR), calculated as the area under diastolic phase/systolic increased composite arterial wave reflections and systemic arterial stiffness. The relationships between BDI and study variables report Spearman’s rank correlation coefficients, given the skewed distribution of BDI. Appropriate transformation of non-normally distributed variables was performed prior to multivariate analyses.
Mean age was 49 ± 10 years, 35% were men, and African Americans constituted 39% of the study population. Prevalence of hypertension, diabetes, hyperlipidemia, and active smoking were 28%, 6%, 25%, and 10%, respectively. Mean BDI-II score was 6.7 ± 7.0; hypertensives and smokers scored ∼3 points higher than their counterparts (p < 0.002, for both), and scores correlated positively with resting heart rate, body mass index, and fasting triglycerides levels (r = 0.12, 0.18, and 0.13, respectively; p < 0.001 for all).
Higher BDI scores correlated with higher AIX (r = 0.09; p = 0.008) and C-reactive protein (CRP) (r = 0.25; p < 0.001), as well as lower SEVR (r = –0.11; p = 0.001) and total glutathione levels (r = –0.12; p < 0.001). Multivariable adjustment for age, sex, race, height, weight, diabetes, hypertension, hyperlipidemia, smoking, and study cohort confirmed an independent association between higher BDI scores and higher AIX (R = 0.59; β = 0.07; p = 0.016) and CRP levels (R = 0.4; β = 0.19; p < 0.001), as well as lower SEVR levels (R = 0.43; β = –0.06; p = 0.038) and total glutathione (R = 0.25; β = –0.1; p = 0.004). Similarly, subject groups with worsening depressive symptoms (none, minimal, and mild to severe) had progressively higher AIX and CRP, as well as lower SEVR and glutathione (p < 0.001 for trend, for all).
Significant interaction effects between physical activity and BDI scores were evident for CRP, AIX, and SEVR (F = 3.3, 3.6, and 4.7; p = 0.006, p = 0.003, and p < 0.001, respectively) (Figure 1). Thus, vascular stiffening and systemic inflammation that accompany worsening depressive symptoms were more pronounced in sedentary subjects, and these relationships were attenuated in subjects engaged in regular moderate to vigorous physical activity.
Depressive symptoms forecast worsened morbidity and mortality across various patient populations including those with CVD. We previously reported increased inflammatory signaling in women with clinical depression and suspected CVD. We now report in a large urban population with adequate representation of women and Blacks that even the presence of minimal depressive symptoms is associated with higher systemic oxidative and inflammatory burden, as well as augmented arterial wave reflections, irrespective of concomitant CVD risk or demographic characteristics. Moreover, regular physical activity significantly modulates this relationship whereby subjects undertaking regular exercise have a lower burden of subclinical CVD markers even in the presence of depressive symptoms.
Our findings highlight potential mechanisms by which depressive disorders are linked to CVD risk, and support the routine assessment of depressive symptoms to improve CVD risk stratification. Physical exercise appears to prevent the adverse cardiovascular consequences of depression, but these findings need to be confirmed in a randomized trial.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation