- Email: [email protected]
Depressive symptoms and inflammation among heart failure patients
Depressive symptoms and inflammation among heart failure patients Amy K. Ferketich, PhD,a Jeanette Pohorence Ferguson, BS,b and Philip F. Binkley, MD, MPHc Columbus, Ohio
Background Psychological depression has been linked to heart failure, both an antecedent to and as a risk factor for poor outcomes among patients with existing heart failure. Elevated levels of proinflammatory cytokines have been proposed as a possible physiological link between the 2 conditions. The objective of this study was to examine the proinflammatory cytokines interleukin (IL)-6, IL-1h, and tumor necrosis factor-alpha (TNFa) in heart failure patients with and without elevated symptoms of depression. Methods
Thirty-two heart failure patients were recruited from an outpatient heart failure clinic. Depressive symptoms were measured with the Beck Depression Inventory (BDI), and a patient was classified as having elevated symptoms of depression if he/she scored z10. The cognitive-affective subscale score of the BDI, which measures depressed mood independent of physical symptoms, was also examined.
Results In the multiple linear regression models controlling for age, sex, smoking, and antidepressant medication use, there was no relation between BDI score and IL - 6 ( P = .7612) or IL-1h ( P = .8261). However, there was a statistically significant positive relation between BDI score and TNFa ( P = .0374). There was also a significant relation between an elevated cognitive-affective score and TNFa ( P = .0322) but no association with IL-6 ( P = .8593) or IL-1h ( P = .3737). Conclusions The association between TNFa and the cognitive-affective subscale, which eliminates the physical signs and symptoms that are shared by depression and heart failure, demonstrates a depression-specific activation of proinflammatory cytokines that may promote disease progression and mortality in patients with heart failure. (Am Heart J 2005;150:132- 6.) Many studies have linked depression to heart disease, both an antecedent1-8 to and as a risk factor for poor outcomes among patients with existing disease,9 -12 including heart failure. Elevated levels of proinflammatory cytokines have been proposed as a possible physiological link between depression and morbidity and mortality associated with heart disease.13 Proinflammatory cytokines exert negative effects on cardiac function, including the promotion of left ventricular remodeling, induction of contractile dysfunction, and uncoupling myocardial h-adrenergic receptors.14 In animal models, tumor necrosis factor-alpha (TNFa), interleukin (IL)-6, and IL-2 are related to negative inotropic activity in a concentration-dependent From the aSchool of Public Health, Division of Epidemiology and Biostatistics and b Department of Pathology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio, and cDivision of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Columbus, Ohio. The study was supported by NHLBI/NIH K24-HL04208, bParadigm Shifts in Clinical Ischemia Detection.Q Submitted May 14, 2004; accepted August 24, 2004. Reprint requests: Amy K. Ferketich, PhD, The Ohio State University School of Public Health, B-116 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. E-mail: [email protected] 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2004.08.029
manner.15 Heart failure patients have been found to have significantly higher levels of proinflammatory cytokines, such as IL-6 and TNFa, compared with healthy controls.16,17 The ability of IL-6 to predict survival was demonstrated in a study of hospitalized patients with heart failure. Increased plasma levels of IL-6 were found to be a strong predictor of survival, after controlling for ejection fraction (EF) and plasma norepinephrine.18 This finding was replicated in the Intervention in Myocarditis and Acute Cardiomyopathy study, where elevated levels of IL-6 were predictive of poorer survival.19 Thus, there is evidence to suggest that proinflammatory cytokines, in particular IL-6 and TNFa, are elevated in heart failure patients. Elevated levels of proinflammatory cytokines, in particular IL-6, IL-1h, and TNFa, have been repeatedly associated with major depressive disorder.20-28 In addition to the studies that have examined levels of proinflammatory cytokines in patients with a diagnosis of major depressive disorder, some reports have focused on individuals who have elevated symptoms of depression and not necessarily a diagnosis of major depression. Suarez et al30 found that symptoms of depression, measured using the Beck Depression Inventory (BDI),29,31 were significantly associated with levels of IL-1h and TNFa. Another study reported a significant
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Ferketich, Ferguson, and Binkley 133
Table I. Characteristics of patients, by depressive symptom status
Table II. Mean, SD, and median proinflammatory cytokine levels, by depressive symptom status
Depression status Variable Age EF Body mass index % Women % Smoker % White
BDI z z10 (n = 14) g
BDI bb10 (n = 18)
52.1 F 10.9 26.9 F 7.2 33.2 F 5.3 50.0% 14.3% 92.9%
57.7 F 9.1 28.1 F 10.9 31.3 F 6.5 27.8% 5.6% 55.6%
Continuous data are expressed as the mean F SD.
relation between depressive symptoms and levels of TNFa and IL-6 in an elderly sample.32 It is not entirely clear if depression would further heighten the inflammatory response among heart failure patients. If so, this could be a possible mechanism through which depression leads to morbidity and mortality. The objective of this study was to compare heart failure patients with and without symptoms of depression with respect to the proinflammatory cytokines IL-6, IL-1h, and TNFa.
Methods Patients were recruited from the heart failure clinic at The Ohio State University between October 2002 and December 2003. Both newly diagnosed patients and patients who had heart failure for an extended period were eligible to participate. All patients had a diagnosis of heart failure (ischemic or nonischemic), were at least 18 years old, and were not awaiting cardiac transplantation. Exclusion criteria included the following: autoimmune disease or any other known condition that would alter cytokine levels, cancer, severe mental illness or cognitive dysfunction, or any other noncardiac life-threatening condition. The institutional review board at The Ohio State University approved this study, and all subjects provided written informed consent before participating. Depressive symptoms were measured with the BDI.29,31 The standard cut point of z10 was used to classify patients with elevated symptoms of depression. In addition to the total BDI score, the cognitive-affective subscale score33,34 was evaluated to allow segregation of depressive symptoms that may be attributable to the process of heart failure from those caused by intrinsic affective changes. The BDI scores among patients with heart failure could be inflated because of the overlap in depressive symptoms and the physical symptoms associated with cardiomyopathy, such as fatigability, weight loss, and sleep disturbance. Evaluation of the cognitive-affective subscale score will facilitate examination of the influence of depressed mood and depressed thinking on cardiovascular function. The cytokines were measured through the use of commercial ACE Enzyme Immunometric Assay kits (Cayman Chemical Co). Patient plasma samples were prepared according to the protocol provided by the company and run in duplicate. After the enzyme-linked immunosorbent assay reactions were run,
Depression status BDI z z10 (n = 14) g
BDI bb10 (n = 18)
Variable
Mean ± SD
Median
Mean ± SD
Median
TNFa (pg/mL) IL-6 (pg/mL) IL-1h (pg/mL)
4.9 F 3.8
4.2
2.7 F 1.8
2.5
5.9 F 2.7
4.6
5.1 F 2.6
4.9
4.4 F 2.1
4.3
3.6 F 2.3
2.8
absorbance readings were obtained using an Elx 808 plate reader and KC junior version 1.21 computer program (Bio-Tek Instruments Inc). The readings were then exported into Microsoft Excel, and the results for each patient sample were averaged together for use in further statistical analysis. Not all patients who consented to participate in the study had measures of cytokines for various reasons. The patients who did have cytokine measures were compared with those who did not with respect to age, body mass index, sex, smoking status, race, BDI score, and EF to determine if there were any significant differences between the 2 groups that could impose bias. Any differences between the 2 groups were included in the analysis as covariates. Linear regression models were fit to the cytokine data. The primary independent variable was elevated depressive symptoms; age, smoking, obesity, and antidepressant medication use were included as potential confounding variables. The residuals were checked for the assumptions of normality and equal variances. If these assumptions were not met with the raw data, a transformation was applied to the outcome data (square root or natural logarithm).
Results Fifty patients were recruited into the study. The average age of the sample was 55.7 (SD 9.9) years, and the average EF was 26.4% (SD 9.5%). The majority of patients were white (78%) and men (64%), which is similar to the characteristics of all outpatients seen for heart failure at the University Medical Center. Only 32 patients had a measure of IL-6 and IL-1h (for technical reasons, only 30 patients had data on TNFa); however, these patients did not differ from the 18 patients without an assessment with respect to age, body mass index, sex, smoking status, race, BDI score, or EF. Patient characteristics, by depression status, are presented in Table I. The group with scores z10 on the BDI was younger, had a lower EF, and had more women, smokers, and whites compared with the group with lower BDI scores. The proinflammatory cytokines were not significantly intercorrelated. The Spearman correlation coefficient for
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134 Ferketich, Ferguson, and Binkley
Figure 1
Box plots of square root–transformed cytokines by depressive symptom classification.
IL-6 and TNFa was 0.09, and for IL-6 and IL-1h, it was 0.21. The correlation coefficient for TNFa and IL-1h was 0.05. Table II contains the descriptive statistics for the proinflammatory cytokines by depression status. Three multiple linear regression models were fit to the data, 1 for each outcome. The residuals from all 3 models were examined, and the assumptions of normality and equal variances were not satisfied by graphical interpretation of the residuals. A square-root transformation and a natural log transformation of the outcome variables were applied to each cytokine, and the model residuals were reexamined. The models from the square root–transformed data had residuals that more closely met the assumptions of normality and equal variances compared with the models from the natural log-transformed data. Therefore, the square root– transformed cytokine data were used in all further analyses. The distribution of the square root–transformed data, by depressive symptom status, is presented in Figure 1. For patients who scored z10 on the BDI, the distributions of square root–transformed TNFa and IL-1h are shifted to the right of the distributions for patients with scores b10 on the BDI. In the multiple linear regression models controlling for age, sex, smoking, and antidepressant medication use, there was no relation between BDI score and IL-6
Table III. Standardized regression coefficients and P values associated with an elevated BDI score and an elevated cognitiveaffective subscale score for each square root–transformed proinflammatory cytokine
Cytokine TNFa IL-6 IL-1h
Elevated BDI (BDI z z10) g Standardized coefficient P 0.43 0.06 0.04
.0374 .7612 .8261
Elevated cognitive-affective score Standardized coefficient 0.45 0.03 0.18
P .0322 .8593 .3737
( P = .7612) or IL-1h ( P = .8261). However, there was a statistically significant relation between the BDI score and square root–transformed TNFa ( P = .0374). Patients who scored z10 on the BDI had a significantly higher level of square root–transformed TNFa compared with patients who scored b10. Table III contains the standardized parameter estimates associated with BDI score for each outcome. The cognitive-affective subscale scores of the BDI were also examined. The data were dichotomized using the median value (4 in these data) as the cut point. The
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results were similar to the total BDI score results. That is, in the multivariable regression model, there was a significant relation between an elevated cognitiveaffective score and TNFa ( P = .0322), and no association with IL-6 ( P = .8593) or IL-1h ( P = .3737). The standardized regression coefficients associated with the cognitive-affective subscale score for each proinflammatory cytokine are presented in Table III.
Discussion The results of this study indicate that heart failure patients who have more depressive symptoms according to the BDI score have significantly higher levels of the proinflammatory cytokine TNFa compared with their nondepressed counterparts. There were no differences in the levels of IL-6 or IL-1h between patients with and patients without depressive symptoms. When examining the effect of the cognitive-affective subscale score on the levels of the proinflammatory cytokines, similar results were found. This is an important finding because the total BDI score may be influenced by both an intrinsic cognitive-affective disorder as well as the physical symptoms of heart failure. The fact that the relation was still present when the physical depressive symptoms were removed from the BDI total score suggests that there might be a true association between depression and TNFa in heart failure patients. It is not clear why similar relations between elevated symptoms of depression and levels of IL-6 and IL-1h were not found. The patients without symptoms of depression had higher levels of IL-6 than other studies have reported. Healthy volunteers in the depressed versus nondepressed studies had average IL-6 levels that ranged from 1.5 to 2.5 pg/mL.26,27,32 In the present study, the average IL-6 among patients without depressive symptoms was 5.1 pg/mL. Likely, the heart failure state contributed to the higher level of IL-6. Alternatively, the small sample size could have contributed to the lack of significant findings. Perhaps if the sample of patients had been larger, significant differences would have been found. In the present study, the power estimates for detecting significant differences between patients with and without elevated symptoms of depression with respect to IL-6 and IL-1h were 16% and 18%, respectively. TNFa has been examined extensively in heart failure patients. In a group of class IV heart failure patients undergoing evaluation for cardiac transplantation, the patients who died or required a left ventricular assist device within the first 15 days had significantly higher levels of TNFa than their counterparts who did not experience such an outcome.35 Liu and Zhao examined the effect of heart failure treatments on circulating levels of TNFa.36 They found that only patients who improved by at least 1 functional class level, after 72 hours of treatment, experienced a significant decline in TNFa.
Ferketich, Ferguson, and Binkley 135
The key implication in our finding is that increased depressive symptoms are associated with elevation of TNFa apart from the process of heart failure itself. Therefore, increases in TNFa could possibly provide a mechanistic basis for the additive effect of depression on adverse outcomes in heart failure. However, these findings must be replicated in larger samples of patients and, ideally, samples that include patients from more than one heart failure clinic. It is possible that this sample of patients was unique with respect to the association between depressive symptoms and the levels of proinflammatory cytokines. Confirmatory studies using larger and more diverse patient samples will add strong support to the hypothesis of an association between depressive symptoms and inflammation. In addition, a large prospective study would allow for the examination of depressive symptoms and levels of proinflammatory cytokines on adverse outcomes in heart failure patients. The cross-sectional nature of the present study prohibits concluding a causal association.
References 1. Clouse RE, Lustman PJ, Freedland KE, et al. Depression and coronary heart disease in women with diabetes. Psychosom Med 2003;65:376 - 83. 2. Ferketich AK, Schwartzbaum JA, Frid DJ, et al. Depression as an antecedent to heart disease among women and men in the NHANES I Study. Arch Intern Med 2000;160:1261- 8. 3. Herrmann C, Brand-Driehorst S, Buss U, et al. Effects of anxiety and depression on 5-year mortality in 5,057 patients referred for exercise testing. J Psychosom Res 2000;48:455 - 62. 4. Ford DE, Mead LA, Chang PP, et al. Depression is a risk factor for coronary artery disease in men: the precursors study. Arch Intern Med 1998;158:1422 - 6. 5. Barefoot JC, Schroll M. Symptoms of depression, acute myocardial infarction, and total mortality in a community sample. Circulation 1996;93:1976 - 80. 6. Everson SA, Goldberg DE, Kaplan GA, et al. Hopelessness and risk of mortality and incidence of myocardial infarction and cancer. Psychosom Med 1996;58:113 - 21. 7. Pratt LA, Ford DE, Crum RM, et al. Depression, psychotropic medication, and risk of myocardial infarction: prospective data from the Baltimore ECA follow-up. Circulation 1996;94:3123 - 9. 8. Aromaa A, Raitasalo R, Reunanen A, et al. Depression and cardiovascular diseases. Acta Psychiatr Scand Suppl 1994; 377:77 - 82. 9. Jiang W, Alexander J, Christopher E, et al. Relationship of depression to increased risk of mortality and rehospitalization in patients with congestive heart failure. Arch Intern Med 2000;161:1849 - 56. 10. Whooley MA, Browner WS. Association between depressive symptoms and mortality in older women. Arch Intern Med 1998;158:2129 - 35. 11. Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995;91:999 - 1005. 12. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA 1993;270:1819 - 25.
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13. Pasic J, Levy WC, Sulllivan MD. Cytokines in depression and heart failure. Psychosom Med 2003;65:181 - 93. 14. Blum A, Miller H. Pathophysiological role of cytokines in congestive heart failure. Annu Rev Med 2001;52:15 - 27. 15. Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992;257: 387 - 9. 16. Munger MA, Johnson B, Amber IJ, et al. Circulating concentrations of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1996;77:723 - 7. 17. Aukrust P, Ueland T, Lien E, et al. Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1999;83:376 - 82. 18. Tsutamoto T, Hisanaga T, Wada A, et al. Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol 1998;31:391- 8. 19. McNamara DM, Starling RC, Dee GW, et al. Plasma cytokines in acute cardiomyopathy: evolution over time, correlations with functional studies, and potential role in recovery. Circulation 2000; 102(Suppl S):415. 20. Miller GE, Stetler CA, Carney RM, et al. Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol 2002;90:1279 - 83. 21. Owen BM, Eccleston D, Ferrier IN, et al. Raised levels of plasma interleukin-1h in major and postviral depression. Acta Psychiatr Scand 2001;103:226 - 8. 22. Schlatter J, Ortuno F, Cervera-Enguix S. Differences in interleukins’ patterns between dysthymia and major depression. Eur Psychiatry 2001;16:317 - 9. 23. Lanquillon S, Kriet JC, Shach BA, et al. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmology 2000;22:370 - 9. 24. Levine J, Barak Y, Chengappa KRN, et al. Cerebrospinal cytokine levels in patients with acute depression. Neuropsychobiology 1999;40:171 - 6.
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25. Song C, Lin A, Bonaccorso S, et al. The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression. J Affect Disord 1998;49:211 - 9. 26. Maes M, Bosmans E, De Jongh R, et al. Increased serum IL-6 and IL1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 1997;9:853 - 8. 27. Maes M, Meltzer HY, Bosmans E, et al. Increased plasma concentrations of interleukin-6, soluble interleukin-6 receptor, soluble interleukin-2 receptor and transferring receptor in major depression. J Affect Disord 1995;34:301 - 9. 28. Maes M, Bosmans E, Meltzer HY, et al. Interleukin-1h: a putative mediator of HPA axis hyperactivity in major depression? Am J Psychiatry 1993;150:1189 - 93. 29. Suarez EC, Krishnan RR, Lewis JG. The relation of severity of depressive symptoms to monocyte-associated proinflammatory cytokines and chemokines in apparently healthy men. Psychosom Med 2003;65:362 - 8. 30. Beck AT. Depression: clinical, experimental, and theoretical aspects. New York: Harper and Row Publishers Inc; 1967. 31. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561 - 71. 32. Penninx BWJH, Kritchevsky SB, Yaffe K, et al. Inflammatory markers and depressed mood in older persons: results from the health. Aging and body composition study. Biol Psychiatry 2003; 54:566 - 72. 33. Beck AT, Steer RA, Garbin MG. Psychometric properties of the beck depression inventory: twenty-five hears of evaluation. Clin Psychol Rev 1988;100 - 877. 34. Plumb MM, Holland J. Comparative studies of psychological function in patients with advanced cancer. I: Self-reported depressive symptoms. Psychosom Med 1977;39:264 - 79. 35. MacGowan GA, Mann DL, Kormos RL, et al. Circulating interleukin6 in severe heart failure. Am J Cardiol 1997;79:1128 - 31. 36. Liu L, Zhao SP. The changes of circulating tumor necrosis factor levels in patients with congestive heart failure influenced by therapy. Int J Cardiol 1999;69:77 - 82.
Background Psychological depression has been linked to heart failure, both an antecedent to and as a risk factor for poor outcomes among patients with existing heart failure. Elevated levels of proinflammatory cytokines have been proposed as a possible physiological link between the 2 conditions. The objective of this study was to examine the proinflammatory cytokines interleukin (IL)-6, IL-1h, and tumor necrosis factor-alpha (TNFa) in heart failure patients with and without elevated symptoms of depression. Methods
Thirty-two heart failure patients were recruited from an outpatient heart failure clinic. Depressive symptoms were measured with the Beck Depression Inventory (BDI), and a patient was classified as having elevated symptoms of depression if he/she scored z10. The cognitive-affective subscale score of the BDI, which measures depressed mood independent of physical symptoms, was also examined.
Results In the multiple linear regression models controlling for age, sex, smoking, and antidepressant medication use, there was no relation between BDI score and IL - 6 ( P = .7612) or IL-1h ( P = .8261). However, there was a statistically significant positive relation between BDI score and TNFa ( P = .0374). There was also a significant relation between an elevated cognitive-affective score and TNFa ( P = .0322) but no association with IL-6 ( P = .8593) or IL-1h ( P = .3737). Conclusions The association between TNFa and the cognitive-affective subscale, which eliminates the physical signs and symptoms that are shared by depression and heart failure, demonstrates a depression-specific activation of proinflammatory cytokines that may promote disease progression and mortality in patients with heart failure. (Am Heart J 2005;150:132- 6.) Many studies have linked depression to heart disease, both an antecedent1-8 to and as a risk factor for poor outcomes among patients with existing disease,9 -12 including heart failure. Elevated levels of proinflammatory cytokines have been proposed as a possible physiological link between depression and morbidity and mortality associated with heart disease.13 Proinflammatory cytokines exert negative effects on cardiac function, including the promotion of left ventricular remodeling, induction of contractile dysfunction, and uncoupling myocardial h-adrenergic receptors.14 In animal models, tumor necrosis factor-alpha (TNFa), interleukin (IL)-6, and IL-2 are related to negative inotropic activity in a concentration-dependent From the aSchool of Public Health, Division of Epidemiology and Biostatistics and b Department of Pathology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio, and cDivision of Cardiovascular Medicine, Davis Heart and Lung Research Institute, Columbus, Ohio. The study was supported by NHLBI/NIH K24-HL04208, bParadigm Shifts in Clinical Ischemia Detection.Q Submitted May 14, 2004; accepted August 24, 2004. Reprint requests: Amy K. Ferketich, PhD, The Ohio State University School of Public Health, B-116 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. E-mail: [email protected] 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2004.08.029
manner.15 Heart failure patients have been found to have significantly higher levels of proinflammatory cytokines, such as IL-6 and TNFa, compared with healthy controls.16,17 The ability of IL-6 to predict survival was demonstrated in a study of hospitalized patients with heart failure. Increased plasma levels of IL-6 were found to be a strong predictor of survival, after controlling for ejection fraction (EF) and plasma norepinephrine.18 This finding was replicated in the Intervention in Myocarditis and Acute Cardiomyopathy study, where elevated levels of IL-6 were predictive of poorer survival.19 Thus, there is evidence to suggest that proinflammatory cytokines, in particular IL-6 and TNFa, are elevated in heart failure patients. Elevated levels of proinflammatory cytokines, in particular IL-6, IL-1h, and TNFa, have been repeatedly associated with major depressive disorder.20-28 In addition to the studies that have examined levels of proinflammatory cytokines in patients with a diagnosis of major depressive disorder, some reports have focused on individuals who have elevated symptoms of depression and not necessarily a diagnosis of major depression. Suarez et al30 found that symptoms of depression, measured using the Beck Depression Inventory (BDI),29,31 were significantly associated with levels of IL-1h and TNFa. Another study reported a significant
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Ferketich, Ferguson, and Binkley 133
Table I. Characteristics of patients, by depressive symptom status
Table II. Mean, SD, and median proinflammatory cytokine levels, by depressive symptom status
Depression status Variable Age EF Body mass index % Women % Smoker % White
BDI z z10 (n = 14) g
BDI bb10 (n = 18)
52.1 F 10.9 26.9 F 7.2 33.2 F 5.3 50.0% 14.3% 92.9%
57.7 F 9.1 28.1 F 10.9 31.3 F 6.5 27.8% 5.6% 55.6%
Continuous data are expressed as the mean F SD.
relation between depressive symptoms and levels of TNFa and IL-6 in an elderly sample.32 It is not entirely clear if depression would further heighten the inflammatory response among heart failure patients. If so, this could be a possible mechanism through which depression leads to morbidity and mortality. The objective of this study was to compare heart failure patients with and without symptoms of depression with respect to the proinflammatory cytokines IL-6, IL-1h, and TNFa.
Methods Patients were recruited from the heart failure clinic at The Ohio State University between October 2002 and December 2003. Both newly diagnosed patients and patients who had heart failure for an extended period were eligible to participate. All patients had a diagnosis of heart failure (ischemic or nonischemic), were at least 18 years old, and were not awaiting cardiac transplantation. Exclusion criteria included the following: autoimmune disease or any other known condition that would alter cytokine levels, cancer, severe mental illness or cognitive dysfunction, or any other noncardiac life-threatening condition. The institutional review board at The Ohio State University approved this study, and all subjects provided written informed consent before participating. Depressive symptoms were measured with the BDI.29,31 The standard cut point of z10 was used to classify patients with elevated symptoms of depression. In addition to the total BDI score, the cognitive-affective subscale score33,34 was evaluated to allow segregation of depressive symptoms that may be attributable to the process of heart failure from those caused by intrinsic affective changes. The BDI scores among patients with heart failure could be inflated because of the overlap in depressive symptoms and the physical symptoms associated with cardiomyopathy, such as fatigability, weight loss, and sleep disturbance. Evaluation of the cognitive-affective subscale score will facilitate examination of the influence of depressed mood and depressed thinking on cardiovascular function. The cytokines were measured through the use of commercial ACE Enzyme Immunometric Assay kits (Cayman Chemical Co). Patient plasma samples were prepared according to the protocol provided by the company and run in duplicate. After the enzyme-linked immunosorbent assay reactions were run,
Depression status BDI z z10 (n = 14) g
BDI bb10 (n = 18)
Variable
Mean ± SD
Median
Mean ± SD
Median
TNFa (pg/mL) IL-6 (pg/mL) IL-1h (pg/mL)
4.9 F 3.8
4.2
2.7 F 1.8
2.5
5.9 F 2.7
4.6
5.1 F 2.6
4.9
4.4 F 2.1
4.3
3.6 F 2.3
2.8
absorbance readings were obtained using an Elx 808 plate reader and KC junior version 1.21 computer program (Bio-Tek Instruments Inc). The readings were then exported into Microsoft Excel, and the results for each patient sample were averaged together for use in further statistical analysis. Not all patients who consented to participate in the study had measures of cytokines for various reasons. The patients who did have cytokine measures were compared with those who did not with respect to age, body mass index, sex, smoking status, race, BDI score, and EF to determine if there were any significant differences between the 2 groups that could impose bias. Any differences between the 2 groups were included in the analysis as covariates. Linear regression models were fit to the cytokine data. The primary independent variable was elevated depressive symptoms; age, smoking, obesity, and antidepressant medication use were included as potential confounding variables. The residuals were checked for the assumptions of normality and equal variances. If these assumptions were not met with the raw data, a transformation was applied to the outcome data (square root or natural logarithm).
Results Fifty patients were recruited into the study. The average age of the sample was 55.7 (SD 9.9) years, and the average EF was 26.4% (SD 9.5%). The majority of patients were white (78%) and men (64%), which is similar to the characteristics of all outpatients seen for heart failure at the University Medical Center. Only 32 patients had a measure of IL-6 and IL-1h (for technical reasons, only 30 patients had data on TNFa); however, these patients did not differ from the 18 patients without an assessment with respect to age, body mass index, sex, smoking status, race, BDI score, or EF. Patient characteristics, by depression status, are presented in Table I. The group with scores z10 on the BDI was younger, had a lower EF, and had more women, smokers, and whites compared with the group with lower BDI scores. The proinflammatory cytokines were not significantly intercorrelated. The Spearman correlation coefficient for
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134 Ferketich, Ferguson, and Binkley
Figure 1
Box plots of square root–transformed cytokines by depressive symptom classification.
IL-6 and TNFa was 0.09, and for IL-6 and IL-1h, it was 0.21. The correlation coefficient for TNFa and IL-1h was 0.05. Table II contains the descriptive statistics for the proinflammatory cytokines by depression status. Three multiple linear regression models were fit to the data, 1 for each outcome. The residuals from all 3 models were examined, and the assumptions of normality and equal variances were not satisfied by graphical interpretation of the residuals. A square-root transformation and a natural log transformation of the outcome variables were applied to each cytokine, and the model residuals were reexamined. The models from the square root–transformed data had residuals that more closely met the assumptions of normality and equal variances compared with the models from the natural log-transformed data. Therefore, the square root– transformed cytokine data were used in all further analyses. The distribution of the square root–transformed data, by depressive symptom status, is presented in Figure 1. For patients who scored z10 on the BDI, the distributions of square root–transformed TNFa and IL-1h are shifted to the right of the distributions for patients with scores b10 on the BDI. In the multiple linear regression models controlling for age, sex, smoking, and antidepressant medication use, there was no relation between BDI score and IL-6
Table III. Standardized regression coefficients and P values associated with an elevated BDI score and an elevated cognitiveaffective subscale score for each square root–transformed proinflammatory cytokine
Cytokine TNFa IL-6 IL-1h
Elevated BDI (BDI z z10) g Standardized coefficient P 0.43 0.06 0.04
.0374 .7612 .8261
Elevated cognitive-affective score Standardized coefficient 0.45 0.03 0.18
P .0322 .8593 .3737
( P = .7612) or IL-1h ( P = .8261). However, there was a statistically significant relation between the BDI score and square root–transformed TNFa ( P = .0374). Patients who scored z10 on the BDI had a significantly higher level of square root–transformed TNFa compared with patients who scored b10. Table III contains the standardized parameter estimates associated with BDI score for each outcome. The cognitive-affective subscale scores of the BDI were also examined. The data were dichotomized using the median value (4 in these data) as the cut point. The
American Heart Journal Volume 150, Number 1
results were similar to the total BDI score results. That is, in the multivariable regression model, there was a significant relation between an elevated cognitiveaffective score and TNFa ( P = .0322), and no association with IL-6 ( P = .8593) or IL-1h ( P = .3737). The standardized regression coefficients associated with the cognitive-affective subscale score for each proinflammatory cytokine are presented in Table III.
Discussion The results of this study indicate that heart failure patients who have more depressive symptoms according to the BDI score have significantly higher levels of the proinflammatory cytokine TNFa compared with their nondepressed counterparts. There were no differences in the levels of IL-6 or IL-1h between patients with and patients without depressive symptoms. When examining the effect of the cognitive-affective subscale score on the levels of the proinflammatory cytokines, similar results were found. This is an important finding because the total BDI score may be influenced by both an intrinsic cognitive-affective disorder as well as the physical symptoms of heart failure. The fact that the relation was still present when the physical depressive symptoms were removed from the BDI total score suggests that there might be a true association between depression and TNFa in heart failure patients. It is not clear why similar relations between elevated symptoms of depression and levels of IL-6 and IL-1h were not found. The patients without symptoms of depression had higher levels of IL-6 than other studies have reported. Healthy volunteers in the depressed versus nondepressed studies had average IL-6 levels that ranged from 1.5 to 2.5 pg/mL.26,27,32 In the present study, the average IL-6 among patients without depressive symptoms was 5.1 pg/mL. Likely, the heart failure state contributed to the higher level of IL-6. Alternatively, the small sample size could have contributed to the lack of significant findings. Perhaps if the sample of patients had been larger, significant differences would have been found. In the present study, the power estimates for detecting significant differences between patients with and without elevated symptoms of depression with respect to IL-6 and IL-1h were 16% and 18%, respectively. TNFa has been examined extensively in heart failure patients. In a group of class IV heart failure patients undergoing evaluation for cardiac transplantation, the patients who died or required a left ventricular assist device within the first 15 days had significantly higher levels of TNFa than their counterparts who did not experience such an outcome.35 Liu and Zhao examined the effect of heart failure treatments on circulating levels of TNFa.36 They found that only patients who improved by at least 1 functional class level, after 72 hours of treatment, experienced a significant decline in TNFa.
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The key implication in our finding is that increased depressive symptoms are associated with elevation of TNFa apart from the process of heart failure itself. Therefore, increases in TNFa could possibly provide a mechanistic basis for the additive effect of depression on adverse outcomes in heart failure. However, these findings must be replicated in larger samples of patients and, ideally, samples that include patients from more than one heart failure clinic. It is possible that this sample of patients was unique with respect to the association between depressive symptoms and the levels of proinflammatory cytokines. Confirmatory studies using larger and more diverse patient samples will add strong support to the hypothesis of an association between depressive symptoms and inflammation. In addition, a large prospective study would allow for the examination of depressive symptoms and levels of proinflammatory cytokines on adverse outcomes in heart failure patients. The cross-sectional nature of the present study prohibits concluding a causal association.
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