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Coronary Plaque Volume and Composition Assessed by Computed Tomography Angiography in Patients With Late-Onset Major Depression
& 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved
Psychosomatics 2014:55:243–251
Original Research Reports Coronary Plaque Volume and Composition Assessed by Computed Tomography Angiography in Patients With Late-Onset Major Depression Torben Albert Devantier, M.D., Ph.D., Bjarne Linde Nørgaard, M.D., Ph.D., Kristian Altern Øvrehus, M.D., Ph.D., Mohamed Marwan, M.D., M.Sc., Mikael Kjær Poulsen, M.D., Ph.D., Stephan Achenbach, M.D., Damini Dey, Ph.D., Poul Videbech, M.D., D.M.Sc.
Background: Depression is a stronger predictor for the onset of or death from clinical coronary artery disease than traditional cardiovascular risk factors. The association between depression and coronary artery disease has previously been investigated in non–contrast enhanced computed tomography studies with conflicting results. The aim of this study was to further elucidate the depression-coronary artery disease relation by use of coronary computed tomography angiography. Methods: The calcified and noncalcified coronary plaque volumes were determined by semiautomatic volumetric quantification in 28 patients with late-onset major depression and 27 controls. The calcified plaque proportion, i.e., the calcified plaque volume divided by the total plaque volume, was used to assess the plaque composition. Results: There was no statistically significant
difference in the total (p ¼ 0.48), calcified (p ¼ 0.15), and noncalcified (p ¼ 0.62) plaque volume between patients and controls, and the total plaque volume did not predict depression, odds ratio ¼ 1.001 [95% confidence interval: 0.999–1.003; p ¼ 0.23]. However, the calcified plaque proportion was twice as high in patients compared with controls (14% vs. 7%, p ¼ 0.044). Correspondingly, having depression was associated with an increased calcified plaque proportion of 11.3 [95% confidence interval: 2.63–20.1; p ¼ 0.012] percentage points after adjustment for demographics and cardiovascular risk factors. Conclusion: The proportion of the total coronary plaque volume that was calcified was significantly higher in patients with late-onset major depression than in controls, indicating a difference in plaque composition. (Psychosomatics 2014; 55:243–251)
INTRODUCTION Major depression is associated with myocardial infarction and sudden cardiac death1–3 and is a stronger predictor for the onset of or death from clinical coronary artery disease (CAD) than traditional cardiovascular risk factors, such as hypertension, smoking, diabetes, and dyslipidemia.4 The primary cause of acute coronary syndromes (i.e., unstable angina and myocardial infarction) is an occlusive coronary thrombosis superimposed on a ruptured or eroded plaque.5 Plaque formation is an atherosclerotic process, and Psychosomatics 55:3, May/June 2014
Received August 6, 2013; revised August 30, 2013; accepted August 30, 2013. From Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark; Department of Cardiology, Aarhus University Hospital, Skejby, Denmark; Department of Cardiology, Odense University Hospital, Odense, Denmark; Department of Internal Medicine II, University of Erlangen, Erlangen, Germany; Biomedical Imaging Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA. Send correspondence and reprint requests to Torben Albert Devantier, M.D., Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Skovagervej 2, DK-8240 Risskov, Denmark; e-mail: [email protected] & 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved
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Coronary Plaque Volume and Composition important atherogenic factors such as inflammation, hypothalamic-pituitary-adrenal axis dysfunction, and increased platelet reactivity are associated with major depression.6,7 It is therefore likely that the presence of major depression augments coronary plaque formation or modulates the coronary plaque composition. Coronary artery calcifications can be quantified using non–contrast enhanced multislice computed tomography (CT). The quantity of coronary calcifications is usually expressed as an Agatston score, which is a product of calcified plaque volume and density.8 Over the last decade, several studies have investigated the relation between depression and coronary calcification with conflicting results: roughly half the studies found coronary calcification to be associated with depression,9–17 whereas the other half did not.18–26 The conflicting results emphasize the need for new approaches for investigating the relation between depression and coronary plaque. One apparent problem with non–contrast enhanced CT is that noncalcified plaque and acute coronary syndrome do regularly occur in the absence of coronary calcification.27 Coronary CT angiography allows quantification of both calcified and noncalcified plaque (Figure 1) and, thus, provides information beyond that supplied by non–contrast enhanced CT.
FIGURE 1.
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The aim of this study was to compare calcified and noncalcified coronary plaque volumes, and plaque composition in patients with late-onset major depression with that of nondepressed controls. METHODS The current study was an observational case-control study performed from September 2009 to November 2011. All participants were Caucasians between the ages of 50 and 70 years. Patients (n ¼ 28) were recruited from a psychiatric hospital (Aarhus University Hospital, Risskov, Denmark) (n ¼ 25) or from private psychiatric practices (n ¼ 3). The nondepressed controls were recruited through announcements in local newspapers and were matched to patients according to sex, age, and tobacco use (previous or current vs. no tobacco use). Patients were eligible if they fulfilled the criteria for major depressive disorder according to the International Classification of Diseases, tenth Revision (ICD-10) and had no history of depression before the age of 50 years. Exclusion criteria were imminent suicide intent, on-going compulsory treatment, a history of head trauma causing more than 2 minutes of unconsciousness, mental disorders according to sections F00–F29 of the ICD-10
Semiautomatic Volumetric Analysis of Coronary Plaque on Coronary ct Angiography Images Using Autoplaq. View of the Left Anterior Descending Artery in Three Mutually Perpendicular Planes. (A) Volumetric Plaque Analysis with Manual Eemarcation of a Luminal Centerline and Plaque Endpoints. (B) Yellow Represents Calcified Plaque (CP), Red Represents Noncalcified Plaque (NCP). CP and NCP Volumes were 93.9 mm3 and 166.9 mm3, Respectively.
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Devantier et al. (e.g., organic mental disorders, disorders due to psychoactive substance use, and schizophrenia), epilepsy, history of stroke, significant cardiac arrhythmia (e.g., atrial fibrillation), body mass index 4 35 kg/m2, and compromised kidney function (i.e., creatinine 4 1.19 mg/dl and 4 1.02 mg/dl for men and women, respectively, or estimated glomerular filtration rate o 60 ml/min). Additionally, controls were excluded if they had any history of mental disorders according to the ICD-10. The study was approved by the regional scientific ethical committee for Central Denmark (M-20080211), was registered at the clinicaltrials.gov registry (NCT00818506), and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from each participant. Medical and Psychiatric History, Risk Factor Assessment, and Laboratory Tests Medical and psychiatric history was obtained during a semistructured interview with a trained physician using selected parts of the Schedules for Clinical Assessment in Neuropsychiatry (SCAN, version 2.1).28 Lifetime tobacco use was estimated and converted to cigarette pack-years (1 pack-year was defined as smoking the equivalent of 20 cigarettes per day for 1 year). In the same setting, blood pressure, height, and weight were measured, and blood and urine samples were collected. The use of antidepressant medication was registered and dichotomized into prolonged use (treatment for 6 months or more) or not. Hypertension was defined as systolic blood pressure 4 140 mm Hg, diastolic blood pressure 4 90 mm Hg, or current antihypertensive treatment. Hyperlipidemia was defined as a total cholesterol level 4 5.0 mmol/l, LDL cholesterol 4 3.0 mmol/l, or the use of lipid-lowering medication. Diabetes mellitus was defined as a fasting plasma blood glucose level 4 7.0 mmol/l on 2 separate occasions or treatment with hypoglycemic or antidiabetic medication. Peripheral arterial disease was defined as an ankle-brachial index of less than 0.90. A history of CAD was defined as angina pectoris or a previous episode of myocardial infarction. An echocardiogram was performed, blinded to clinical data, by a trained physician on a GE Vivid E9 ultrasound machine (GE Healthcare, Chalfont St Giles, UK) using a 2.5-MHz transducer, and wall motion index was used to estimate left ventricular ejection fraction using a 16-segment Psychosomatics 55:3, May/June 2014
model.29 Education was measured in years from the first year of primary school. Urinary samples were screened for drugs, and the Alcohol Use Disorders Identification Test (AUDIT), plasma carbohydrate– deficient transferrin, and liver enzymes were used to screen for alcohol dependence. Coronary CT Angiography Imaging Protocol All participants were scanned using a Siemens 64-slice Dual Source CT scanner (Siemens Definition, Siemens Medical Solutions, Forcheim, Germany). If the heart rate was greater than 65 beats per minute at the time of the scan, up to 4 doses of 5-mg metoprolol were administered intravenously. A dose of 0.4-mg sublingual nitroglycerine was administered to all patients before the enhanced scan. An initial electrocardiogram-gated nonenhanced sequential scan (at 65% of RR interval) was performed for calcium scoring. For the enhanced scan, 70–80 ml of iodinated contrast (Iomeron 350, Bracco, Milan, Italy) was injected (5 ml/s) in the antecubital vein followed by a 50 ml saline flush. Contrast transit time was determined by injecting a test bolus of 10 ml of contrast followed by a 50-ml saline chaser at 5 ml/s and measuring the peak enhancement in the ascending aorta. In subjects weighing o 85 kg and with a prescan heart rate o 60/min (n ¼ 33), prospective electrocardiogram-triggered high-pitch spiral acquisition was performed.30 In the rest of the study cohort (n ¼ 22), image acquisition was performed with prospective electrocardiographic gating (65%–75% and 40%–70% of the RR interval in subjects with a heart rate o 65/min and Z 65/min, respectively). Coronary CT angiography was performed using a 100(o 80 kg) or 120- (Z 80 kg) kV tube voltage setting, adaptive tube current with a reference of 370 mAs, 2 32 0.6-mm3 slice collimation, z-flying focal spot, and a gantry rotation of 330 ms. Patient radiation exposures were estimated as the dose-length product multiplied by a chest-region conversion factor (0.014 mSv mGy1 cm1).31 Coronary Plaque Burden Images were reconstructed with a slice thickness of 0.75 mm and a 0.4-mm slice increment. Window level and width were initially displayed at a predefined setting (level 200 Hounsfield Units, width 700 www.psychosomaticsjournal.org
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Coronary Plaque Volume and Composition Hounsfield Units). For optimal visualization, adjustments of the window-level settings were performed at the discretion of the observer. The coronary CT angiography studies were randomly and independently assessed by 2 experienced observers blinded to clinical information using axial images and multiplanar reconstructions on separate workstations (Leonardo Multi-Modality Workstation, Siemens Medical Solutions, Forcheim, Germany). Because of the high interrater reproducibility of coronary artery calcium scoring,32 coronary artery calcifications were quantified (Syngo Calcium Scoring, Siemens Medical Solutions, Forcheim, Germany) by only 1 observer using the Agatston score.8 For the contrast-enhanced scan, a coronary plaque was defined as a visual entity 41 mm2 within the vessel wall that was clearly distinctive from tissue surrounding the vessel. Coronary calcified, noncalcified, and total plaque volumes were estimated with an average score of 3 separate measurements using a previously described and validated semiautomated quantification tool (AutoPlaq, Cedars-Sinai Medical Center, Los Angeles, CA).33,34 Coronary Plaque Composition The plaque composition was assessed by calculating the calcified plaque proportion. The calcified plaque proportion was defined as the calcified plaque volume divided by the total plaque volume (i.e., the sum of calcified and noncalcified plaque volumes). The calcified plaque proportion is expressed as a percentage (100%). Calcified plaque proportion was unobtainable in subjects with zero plaque, who were thus excluded from the plaque composition analysis. The group of participants with presence of any plaque is hereinafter referred to as the plaque composition cohort. Statistical Analyses Baseline variables were compared between patients and controls in both the total study population and the plaque composition cohort. The Mann-Whitney U test and the Student's t-test were used to compare nonparametric and parametric continuous data, respectively. Comparisons of categorical data were performed using the Fisher Exact test. Continuous variables are presented as mean ⫾ standard deviation or median [interquartile range; range] as appropriate. 246
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Coronary plaque volumes were nonnormally distributed even after logarithmic transformation. The relation between total coronary plaque volume and lateonset major depression was assessed using logistic regression. A priori, sex and age were selected as covariates for the adjusted logistic regression model. Logistic regression analysis results are presented as odds ratio [95% confidence interval (CI); p-value]. Multiple linear regression was used to assess the association between calcified plaque proportion and depression. Calcified plaque proportion was the dependent variable and case-control status the independent variable of interest. A priori, sex, age, body mass index, hypertension, hyperlipidemia, and lifetime tobacco use were selected as potential confounders (diabetes and history of CAD were not applicable as covariates owing to their low frequency and absence in controls). The relation between calcified plaque proportion and prolonged use of antidepressants in the patients of the plaque composition cohort was assessed using the Spearman rank-order correlation. All tests were two-tailed and a significance level of 5% was utilized. Analyses were conducted using IBM SPSS Statistics version 20.0.0.1 (IBM Corporation, Armonk, New York, NY). RESULTS A total of 59 subjects were included in the study. One patient was excluded owing to alcohol dependence, 2 owing to absenteeism, and technical issues prevented processing of CT data from 1 patient leaving a total study population of 28 patients and 27 controls. Of the 28 patients, 6 met the criteria for moderate and 22 for severe depression. The median [interquartile range; range] duration of depressive episodes was 24 [10–41; 4–180] months (for cases with recurrent depression [n ¼ 2], the summed durations of all depressive episodes were used). Baseline characteristics for the total study population are displayed in Table 1. Seven patients and 7 controls had a total plaque volume of zero and, thus, were not included in the plaque composition cohort. The proportion of subjects with a total plaque volume of zero was not significantly different between patients and controls, 30% vs. 26%, p 4 0.99. Baseline characteristics in the plaque composition cohort (results not shown) resembled that of the total study population. However, in the plaque composition cohort, mean ⫾ standard deviation body mass index Psychosomatics 55:3, May/June 2014
Devantier et al. TABLE 1.
Baseline Characteristics
Variable Demographics Male sex, count (%) Age, y Education, y Cardiovascular risk factors History of CAD, count (%) Smoking, pack-y, median [IQR; range] Body mass index (kg/m2) Diabetes mellitus, count (%) Hypertension, count (%) Hyperlipidemia, count (%) Peripheral arterial disease, count (%) Left ventricular ejection fraction (%) Creatinine (mg/dl) AD treatment 4 6 months, count (%) Alcohol use, AUDIT score
Controls (n ¼ 27)
Patients (n ¼ 28)
p-Value
14 (52) 59.5 ⫾ 5.0 15.3 ⫾ 2.1
15 (54) 59.9 ⫾ 4.6 14.6 ⫾ 2.6
4 0.99 0.75 0.26
0 (0) 7.3 [0.5–15; 0–49] 25 ⫾ 2.8 0 (0) 12 (44) 20 (74) 0 (0) 59 ⫾ 2.2 0.8 ⫾ 0.2 0 (0) 6.0 ⫾ 3.5
3 (11) 19 [0–31; 0–80] 27 ⫾ 3.8 1 (3.6) 15 (54) 25 (89) 1 (3.6) 58 ⫾ 4.0 0.9 ⫾ 0.2 20 (71) 5.1 ⫾ 4.0
0.24 0.13 0.10 4 0.99 0.59 0.18 4 0.99 0.22 0.091 o 0.001 0.37
Data are presented as mean ⫾ standard deviation unless otherwise specified. All p values are two-tailed and p values o0.05 are displayed with bold. AD ¼ antidepressant; AUDIT ¼ Alcohol Use Disorder Identification Test; CAD ¼ coronary artery disease; IQR ¼ interquartile range.
was higher in patients than in controls, 26.7 ⫾ 4.1 vs. 24.4 ⫾ 2.2 kg/m2, respectively, p ¼ 0.034. Coronary CT Angiography Intravenous β-blockers were administered to 67% of the participants (71% in patients vs. 63% in controls, p ¼ 0.573), resulting in a mean ⫾ standard deviation heart rate during the CT scan of 61 ⫾ 11 beats per minute (range, 45–95 beats per minute). Estimated mean ⫾ standard deviation radiation dose was 3.2 ⫾ 2.0 mSv.
[0–69; 0–418], respectively, p ¼ 0.084. In the plaque composition cohort, the median [interquartile range; range] Agatston score was significantly higher in the patients, 92 [15–321; 0–1710] vs. 45 [0–101; 0–418], p ¼ 0.031. In the total study population, the higher values for total, calcified, and noncalcified plaque volume in patients as compared with controls did not reach statistical significance (Table 2). Moreover, late-onset major depression was not significantly associated with total coronary plaque volume in the unadjusted and adjusted logistic regression analysis, odds ratio ¼ 1.001 [95% CI: 0.999–1.003; p ¼ 0.25] and odds ratio ¼ 1.001 [95% CI: 0.999–1.003; p ¼ 0.23], respectively.
Coronary Plaque Burden There was a trend toward a higher median [interquartile range; range] Agatston score in patients compared with controls, 55 [0–262; 0–1710] vs. 14 TABLE 2.
Coronary Plaque Composition In the plaque composition cohort, the median calcified plaque proportion was twice as high in
Distributions of Coronary Plaque Measures
Variable 3
CP volume (mm ) NCP volume (mm3) Total plaque volume (mm3) CP–proportion (%)*
Controls (n ¼ 27)
Patients (n ¼ 28)
p-Value
3 92 92 7
16 136 172 14
0.15 0.62 0.48 0.044
[0–25; 0–109] [0–385; 0–949] [0–401; 0–1058] [3–14; 0–43]
[0–51; 0–769] [1–394; 0–1108] [2–454; 0–1620] [7–23; 0–47]
Data are reported as median [interquartile range; range]. All p values are two-tailed and p values o0.05 are displayed with bold. CP ¼ calcified plaque; NCP ¼ noncalcified plaque. n
Obtainable only in subjects with any plaque present (the plaque composition cohort), n ¼ 41.
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Coronary Plaque Volume and Composition TABLE 3.
Multiple Linear Regression Assessing the Association Between Coronary Plaque Composition and Late-Onset Major Depression
Independent variables
B
95% CI
p-Value
Model 1 Depression vs. no depression 7.14 0.23–14.5 0.057 Model 2: Model 1 þ sex and age Depression vs. no depression 7.04 0.53–14.6 0.067 Model 3: Model 2 þ BMI, hypertension, hyperlipidemia, and lifetime tobacco use Depression vs. no depression 11.3 2.63–20.1 0.012 Dependent variable is the calcified plaque proportion, %. All p values are two-sided and p values o0.05 are displayed with bold. B ¼ unstandardized regression coefficient; BMI ¼ body mass index.
patients compared with controls (Table 2). Multiple linear regression results are presented in Table 3. Unadjusted comparison of cases and controls showed a trend toward a significant association between late-onset major depression and calcified plaque proportion. After adjustments for demographics and cardiovascular risk factors, however, depression was significantly associated with a higher calcified plaque proportion. It is noteworthy that calcified plaque proportion was not correlated with age, n ¼ 41; r ¼ 0.11; 95% CI: 0.21 to 0.40; p ¼ 0.50, or prolonged use of antidepressants (patients only), n ¼ 21; r ¼ 0.00; 95% CI: 0.43 to 0.43; p 4 0.99. DISCUSSION In this study, the calcified, noncalcified, and total coronary plaque volumes were higher in patients with late-onset major depression compared with nondepressed controls, but the differences between groups did not reach statistical significance. However, the calcified to the total plaque volume ratio was twice as high in the patients (14% vs. 7%; p ¼ 0.044) indicating a difference in plaque composition between groups. Accordingly, having depression was associated with an increased calcified plaque proportion of 11.3 [95% CI: 2.63–20.1; p ¼ 0.012] percentage points after adjustment for demographics and cardiovascular risk factors. To the best of our knowledge, the present study is the first to use coronary CT angiography to assess the relation between depression and coronary plaque. The 248
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hitherto largest non–contrast enhanced CT study found no association between depression and Agatston score in 6814 middle-aged to elderly men and women.20 The 2 largest prospective studies show conflicting results: Stewart et al.17 found depression to increase the odds of incident coronary calcification by 61% in 2171 middle-aged men and women, whereas Newson et al.24 found no association in 1792 older adults. Overall, roughly half of the non–contrast enhanced CT studies available have found coronary calcification to be associated with depression,9–17 whereas the other half has not.18–26 We found a significant difference in the coronary plaque composition between patients and controls despite fairly similar plaque volumes. This study thus indicates that investigating plaque quantities alone cannot preclude a modulating effect of depression on plaque formation. This may be clinically relevant because plaque rupture risk depends more on plaque composition than on the size of a plaque.35 In this study, the calcified plaque proportion was twice as high in patients than in controls. Vascular calcification was previously thought to be a passive accumulation of calcium and phosphate, but now appears to be a regulated process involving induction of osteogenesis and reduced inhibition of mineralization.36 It is generally recognized that lipid deposits destabilize plaques, but the role of plaque calcification is less evident. In an in vitro stress test study of 20 human coronary lesions, Huang et al.37 found no destabilizing effect of calcifications on plaques but, concurrently, state that calcifications may still induce plaque defects in vivo. A destabilizing effect of calcifications on plaques in vivo is supported by Ehara et al.38 finding that a pattern of spotty calcification is more frequent in acute myocardial infarction than in stable and unstable angina pectoris. Another study has shown that calcification is negatively correlated with the degree of plaque macrophage infiltration, a factor associated with atherosclerosis and plaque instability.39 Paradoxically, the latter study also found a positive association between calcification and the relative size of the plaque lipid core.39 Altogether, the available data suggest that plaque calcification is a dynamic process that may influence plaque stability. Our finding of increased calcified plaque proportion in patients with late-onset depression thus seems important to promote the understanding of CAD in depression. Psychosomatics 55:3, May/June 2014
Devantier et al. The use of calcified plaque proportion for assessment of coronary plaque composition is, to the best of our knowledge, unprecedented. Consequently, studies are needed to understand how the calcified plaque proportion relates to clinical CAD. Therefore, the implications of the present study are primarily methodologic rather than clinical. Nonetheless, the present results urge health professionals to carefully consider CAD and to advocate reductions of lifestyle-related cardiovascular risk factors when treating depressed patients, especially patients with late-onset major depression. Methodologic Considerations The study cohort was small. Although not statistically significant, the median total plaque volume was notably higher in patients when compared with controls (172 mm3 vs. 92 mm3), and thus it may be speculated that the lack of statistical significance in plaque volume analyses represents a type II error. Therefore, larger studies investigating calcified and noncalcified plaque volumes in depressed patients are needed. The patients in the present study represented the severe end of the depression spectrum as all patients were either moderately or severely depressed, and most were hospitalized because of depression. Therefore, the results of this study may not be generalizable to most depressed patients. The long disease durations and thorough observation during hospitalization, however, contribute to an increased validity of the depression diagnoses. The study size precluded categorization of patients into subgroups based on depression duration and severity, characteristics that are likely to affect the interaction between depression and plaque formation and therefore should be considered in future studies. Antidepressant medication may affect plaque formation. The study design precluded comprehensive analyses of the effect of antidepressants on plaque composition, but the lack of
correlation between calcified plaque proportion and prolonged use of antidepressants does dispute that such an effect would be substantial. Finally, stratification of plaque into calcified or noncalcified plaque is crude when compared with histopathologic classification schemes. The presence or absence of calcium in a plaque does nonetheless reflect a difference in the plaque morphology.40 Furthermore, coronary CT angiography has limitations when differentiating between plaque components (e.g., lipid-rich and fibrotic components).27 A superior per plaque analysis could be performed in vivo using intravascular ultrasound, but, as opposed to CT angiography, intravascular ultrasound is an invasive and time-consuming procedure not suitable for examining the complete coronary artery tree.
Conclusion Although the coronary plaque burden was comparable in patients and in controls, late-onset major depression was associated with an increased calcified plaque proportion, reflecting a difference in the coronary plaque composition between groups. Future studies should evaluate the plaque composition, in addition to the plaque burden, when investigating coronary plaque in relation to depression, and health professionals should consider CAD when treating depressed patients. Disclosure: Cedars-Sinai Medical Center (Los Angeles, CA) may receive royalties for the licensing of the AutoPlaq software, a minority of which may be distributed to Damini Dey. All other authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. This work was funded by Aarhus University, the Central Denmark Region, the Danish Ministry of Science, Technology, and Innovation, and Augustinus Fonden, Denmark.
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20. Diez Roux AV, Ranjit N, Powell L, et al: Psychosocial factors and coronary calcium in adults without clinical cardiovascular disease. Ann Intern Med 2006; 144(11): 822–831 21. Taylor AJ, Arora NS, Bindeman J, Bhattari S, Feuerstein IM, O'Malley PG: Conventional, emerging, heredity, lifestyle, and psychosocial coronary risk factors: relationships to subclinical atherosclerosis. Prev Cardiol 2006; 9(1):25–32 22. Smith TW, Uchino BN, Berg CA, et al: Associations of selfreports versus spouse ratings of negative affectivity, dominance, and affiliation with coronary artery disease: where should we look and who should we ask when studying personality and health? Health Psychol 2008; 27(6):676–684 23. Lewis TT, Everson-Rose SA, Colvin A, Matthews K, Bromberger JT, Sutton-Tyrrell K: Interactive effects of race and depressive symptoms on calcification in African American and white women. Psychosom Med 2009; 71(2): 163–170 24. Newson RS, Hek K, Luijendijk HJ, Hofman A, Witteman JCM, Tiemeier H: Atherosclerosis and incident depression in late life. Arch Gen Psychiatry 2010; 67(11):1144–1151 25. Rozanski A, Gransar H, Kubzansky LD, et al: Do psychological risk factors predict the presence of coronary atherosclerosis? Psychosom Med 2011; 73(1):7–15 26. Devantier TA, Nørgaard BL, Sand NP, et al: Lack of correlation between depression and coronary artery calcification in a non-selected Danish population. Psychosomatics 2013; 54(5):458–465 27. Gallino A, Stuber M, Crea F, et al: In vivo imaging of atherosclerosis. Atherosclerosis 2012; 224(1):25–36 28. Wing JK, Babor T, Brugha T, et al: SCAN. Schedules for clinical assessment in neuropsychiatry. Arch Gen Psychiatry 1990; 47(6):589–593 29. Lang RM, Bierig M, Devereux RB, et al: Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18(12):1440–1463 30. Achenbach S, Marwan M, Ropers D, et al: Coronary computed tomography angiography with a consistent dose below 1 mSv using prospectively electrocardiogram-triggered high-pitch spiral acquisition. Eur Heart J 2010; 31(3):340–346 31. Halliburton SS, Abbara S, Chen MY, et al: SCCT guidelines on radiation dose and dose-optimization strategies in cardiovascular CT. J Cardiovasc Comput Tomogr 2011; 5(4): 198–224 32. Diederichsen ACP, Sand NP, Nørgaard BL, et al: Discrepancy between coronary artery calcium score and HeartScore in middle-aged Danes: the DanRisk study. Eur J Prev Cardiol 2012; 19(3):558–564 33. Dey D, Cheng VY, Slomka PJ, et al: Automated 3dimensional quantification of noncalcified and calcified coronary plaque from coronary CT angiography. J Cardiovasc Comput Tomogr 2009; 3(6):372–382
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Devantier et al. 34. Dey D, Schepis T, Marwan M, Slomka PJ, Berman DS, Achenbach S: Automated three-dimensional quantification of noncalcified coronary plaque from coronary CT angiography: comparison with intravascular US. Radiology 2010; 257(2):516–522 35. Ylä-Herttuala S, Bentzon JF, Daemen M, et al: Stabilisation of atherosclerotic plaques. Position paper of the European Society of Cardiology (ESC) working group on atherosclerosis and vascular biology. Thromb Haemost 2011; 106(1):1–19 36. Johnson RC, Leopold JA, Loscalzo J: Vascular calcification: pathobiological mechanisms and clinical implications. Circ Res 2006; 99(10):1044–1059
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37. Huang H, Virmani R, Younis H, Burke AP, Kamm RD, Lee RT: The impact of calcification on the biomechanical stability of atherosclerotic plaques. Circulation 2001; 103(8):1051–1056 38. Ehara S, Kobayashi Y, Yoshiyama M, et al: Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study. Circulation 2004; 110(22):3424–3429 39. Burke AP, Weber DK, Kolodgie FD, Farb A, Taylor AJ, Virmani R: Pathophysiology of calcium deposition in coronary arteries. Herz 2001; 26(4):239–244 40. Insull W: The pathology of atherosclerosis: plaque development and plaque responses to medical treatment. Am J Med 2009; 122(1 Suppl):3–14
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Psychosomatics 2014:55:243–251
Original Research Reports Coronary Plaque Volume and Composition Assessed by Computed Tomography Angiography in Patients With Late-Onset Major Depression Torben Albert Devantier, M.D., Ph.D., Bjarne Linde Nørgaard, M.D., Ph.D., Kristian Altern Øvrehus, M.D., Ph.D., Mohamed Marwan, M.D., M.Sc., Mikael Kjær Poulsen, M.D., Ph.D., Stephan Achenbach, M.D., Damini Dey, Ph.D., Poul Videbech, M.D., D.M.Sc.
Background: Depression is a stronger predictor for the onset of or death from clinical coronary artery disease than traditional cardiovascular risk factors. The association between depression and coronary artery disease has previously been investigated in non–contrast enhanced computed tomography studies with conflicting results. The aim of this study was to further elucidate the depression-coronary artery disease relation by use of coronary computed tomography angiography. Methods: The calcified and noncalcified coronary plaque volumes were determined by semiautomatic volumetric quantification in 28 patients with late-onset major depression and 27 controls. The calcified plaque proportion, i.e., the calcified plaque volume divided by the total plaque volume, was used to assess the plaque composition. Results: There was no statistically significant
difference in the total (p ¼ 0.48), calcified (p ¼ 0.15), and noncalcified (p ¼ 0.62) plaque volume between patients and controls, and the total plaque volume did not predict depression, odds ratio ¼ 1.001 [95% confidence interval: 0.999–1.003; p ¼ 0.23]. However, the calcified plaque proportion was twice as high in patients compared with controls (14% vs. 7%, p ¼ 0.044). Correspondingly, having depression was associated with an increased calcified plaque proportion of 11.3 [95% confidence interval: 2.63–20.1; p ¼ 0.012] percentage points after adjustment for demographics and cardiovascular risk factors. Conclusion: The proportion of the total coronary plaque volume that was calcified was significantly higher in patients with late-onset major depression than in controls, indicating a difference in plaque composition. (Psychosomatics 2014; 55:243–251)
INTRODUCTION Major depression is associated with myocardial infarction and sudden cardiac death1–3 and is a stronger predictor for the onset of or death from clinical coronary artery disease (CAD) than traditional cardiovascular risk factors, such as hypertension, smoking, diabetes, and dyslipidemia.4 The primary cause of acute coronary syndromes (i.e., unstable angina and myocardial infarction) is an occlusive coronary thrombosis superimposed on a ruptured or eroded plaque.5 Plaque formation is an atherosclerotic process, and Psychosomatics 55:3, May/June 2014
Received August 6, 2013; revised August 30, 2013; accepted August 30, 2013. From Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark; Department of Cardiology, Aarhus University Hospital, Skejby, Denmark; Department of Cardiology, Odense University Hospital, Odense, Denmark; Department of Internal Medicine II, University of Erlangen, Erlangen, Germany; Biomedical Imaging Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA. Send correspondence and reprint requests to Torben Albert Devantier, M.D., Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Skovagervej 2, DK-8240 Risskov, Denmark; e-mail: [email protected] & 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved
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Coronary Plaque Volume and Composition important atherogenic factors such as inflammation, hypothalamic-pituitary-adrenal axis dysfunction, and increased platelet reactivity are associated with major depression.6,7 It is therefore likely that the presence of major depression augments coronary plaque formation or modulates the coronary plaque composition. Coronary artery calcifications can be quantified using non–contrast enhanced multislice computed tomography (CT). The quantity of coronary calcifications is usually expressed as an Agatston score, which is a product of calcified plaque volume and density.8 Over the last decade, several studies have investigated the relation between depression and coronary calcification with conflicting results: roughly half the studies found coronary calcification to be associated with depression,9–17 whereas the other half did not.18–26 The conflicting results emphasize the need for new approaches for investigating the relation between depression and coronary plaque. One apparent problem with non–contrast enhanced CT is that noncalcified plaque and acute coronary syndrome do regularly occur in the absence of coronary calcification.27 Coronary CT angiography allows quantification of both calcified and noncalcified plaque (Figure 1) and, thus, provides information beyond that supplied by non–contrast enhanced CT.
FIGURE 1.
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The aim of this study was to compare calcified and noncalcified coronary plaque volumes, and plaque composition in patients with late-onset major depression with that of nondepressed controls. METHODS The current study was an observational case-control study performed from September 2009 to November 2011. All participants were Caucasians between the ages of 50 and 70 years. Patients (n ¼ 28) were recruited from a psychiatric hospital (Aarhus University Hospital, Risskov, Denmark) (n ¼ 25) or from private psychiatric practices (n ¼ 3). The nondepressed controls were recruited through announcements in local newspapers and were matched to patients according to sex, age, and tobacco use (previous or current vs. no tobacco use). Patients were eligible if they fulfilled the criteria for major depressive disorder according to the International Classification of Diseases, tenth Revision (ICD-10) and had no history of depression before the age of 50 years. Exclusion criteria were imminent suicide intent, on-going compulsory treatment, a history of head trauma causing more than 2 minutes of unconsciousness, mental disorders according to sections F00–F29 of the ICD-10
Semiautomatic Volumetric Analysis of Coronary Plaque on Coronary ct Angiography Images Using Autoplaq. View of the Left Anterior Descending Artery in Three Mutually Perpendicular Planes. (A) Volumetric Plaque Analysis with Manual Eemarcation of a Luminal Centerline and Plaque Endpoints. (B) Yellow Represents Calcified Plaque (CP), Red Represents Noncalcified Plaque (NCP). CP and NCP Volumes were 93.9 mm3 and 166.9 mm3, Respectively.
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Devantier et al. (e.g., organic mental disorders, disorders due to psychoactive substance use, and schizophrenia), epilepsy, history of stroke, significant cardiac arrhythmia (e.g., atrial fibrillation), body mass index 4 35 kg/m2, and compromised kidney function (i.e., creatinine 4 1.19 mg/dl and 4 1.02 mg/dl for men and women, respectively, or estimated glomerular filtration rate o 60 ml/min). Additionally, controls were excluded if they had any history of mental disorders according to the ICD-10. The study was approved by the regional scientific ethical committee for Central Denmark (M-20080211), was registered at the clinicaltrials.gov registry (NCT00818506), and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from each participant. Medical and Psychiatric History, Risk Factor Assessment, and Laboratory Tests Medical and psychiatric history was obtained during a semistructured interview with a trained physician using selected parts of the Schedules for Clinical Assessment in Neuropsychiatry (SCAN, version 2.1).28 Lifetime tobacco use was estimated and converted to cigarette pack-years (1 pack-year was defined as smoking the equivalent of 20 cigarettes per day for 1 year). In the same setting, blood pressure, height, and weight were measured, and blood and urine samples were collected. The use of antidepressant medication was registered and dichotomized into prolonged use (treatment for 6 months or more) or not. Hypertension was defined as systolic blood pressure 4 140 mm Hg, diastolic blood pressure 4 90 mm Hg, or current antihypertensive treatment. Hyperlipidemia was defined as a total cholesterol level 4 5.0 mmol/l, LDL cholesterol 4 3.0 mmol/l, or the use of lipid-lowering medication. Diabetes mellitus was defined as a fasting plasma blood glucose level 4 7.0 mmol/l on 2 separate occasions or treatment with hypoglycemic or antidiabetic medication. Peripheral arterial disease was defined as an ankle-brachial index of less than 0.90. A history of CAD was defined as angina pectoris or a previous episode of myocardial infarction. An echocardiogram was performed, blinded to clinical data, by a trained physician on a GE Vivid E9 ultrasound machine (GE Healthcare, Chalfont St Giles, UK) using a 2.5-MHz transducer, and wall motion index was used to estimate left ventricular ejection fraction using a 16-segment Psychosomatics 55:3, May/June 2014
model.29 Education was measured in years from the first year of primary school. Urinary samples were screened for drugs, and the Alcohol Use Disorders Identification Test (AUDIT), plasma carbohydrate– deficient transferrin, and liver enzymes were used to screen for alcohol dependence. Coronary CT Angiography Imaging Protocol All participants were scanned using a Siemens 64-slice Dual Source CT scanner (Siemens Definition, Siemens Medical Solutions, Forcheim, Germany). If the heart rate was greater than 65 beats per minute at the time of the scan, up to 4 doses of 5-mg metoprolol were administered intravenously. A dose of 0.4-mg sublingual nitroglycerine was administered to all patients before the enhanced scan. An initial electrocardiogram-gated nonenhanced sequential scan (at 65% of RR interval) was performed for calcium scoring. For the enhanced scan, 70–80 ml of iodinated contrast (Iomeron 350, Bracco, Milan, Italy) was injected (5 ml/s) in the antecubital vein followed by a 50 ml saline flush. Contrast transit time was determined by injecting a test bolus of 10 ml of contrast followed by a 50-ml saline chaser at 5 ml/s and measuring the peak enhancement in the ascending aorta. In subjects weighing o 85 kg and with a prescan heart rate o 60/min (n ¼ 33), prospective electrocardiogram-triggered high-pitch spiral acquisition was performed.30 In the rest of the study cohort (n ¼ 22), image acquisition was performed with prospective electrocardiographic gating (65%–75% and 40%–70% of the RR interval in subjects with a heart rate o 65/min and Z 65/min, respectively). Coronary CT angiography was performed using a 100(o 80 kg) or 120- (Z 80 kg) kV tube voltage setting, adaptive tube current with a reference of 370 mAs, 2 32 0.6-mm3 slice collimation, z-flying focal spot, and a gantry rotation of 330 ms. Patient radiation exposures were estimated as the dose-length product multiplied by a chest-region conversion factor (0.014 mSv mGy1 cm1).31 Coronary Plaque Burden Images were reconstructed with a slice thickness of 0.75 mm and a 0.4-mm slice increment. Window level and width were initially displayed at a predefined setting (level 200 Hounsfield Units, width 700 www.psychosomaticsjournal.org
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Coronary Plaque Volume and Composition Hounsfield Units). For optimal visualization, adjustments of the window-level settings were performed at the discretion of the observer. The coronary CT angiography studies were randomly and independently assessed by 2 experienced observers blinded to clinical information using axial images and multiplanar reconstructions on separate workstations (Leonardo Multi-Modality Workstation, Siemens Medical Solutions, Forcheim, Germany). Because of the high interrater reproducibility of coronary artery calcium scoring,32 coronary artery calcifications were quantified (Syngo Calcium Scoring, Siemens Medical Solutions, Forcheim, Germany) by only 1 observer using the Agatston score.8 For the contrast-enhanced scan, a coronary plaque was defined as a visual entity 41 mm2 within the vessel wall that was clearly distinctive from tissue surrounding the vessel. Coronary calcified, noncalcified, and total plaque volumes were estimated with an average score of 3 separate measurements using a previously described and validated semiautomated quantification tool (AutoPlaq, Cedars-Sinai Medical Center, Los Angeles, CA).33,34 Coronary Plaque Composition The plaque composition was assessed by calculating the calcified plaque proportion. The calcified plaque proportion was defined as the calcified plaque volume divided by the total plaque volume (i.e., the sum of calcified and noncalcified plaque volumes). The calcified plaque proportion is expressed as a percentage (100%). Calcified plaque proportion was unobtainable in subjects with zero plaque, who were thus excluded from the plaque composition analysis. The group of participants with presence of any plaque is hereinafter referred to as the plaque composition cohort. Statistical Analyses Baseline variables were compared between patients and controls in both the total study population and the plaque composition cohort. The Mann-Whitney U test and the Student's t-test were used to compare nonparametric and parametric continuous data, respectively. Comparisons of categorical data were performed using the Fisher Exact test. Continuous variables are presented as mean ⫾ standard deviation or median [interquartile range; range] as appropriate. 246
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Coronary plaque volumes were nonnormally distributed even after logarithmic transformation. The relation between total coronary plaque volume and lateonset major depression was assessed using logistic regression. A priori, sex and age were selected as covariates for the adjusted logistic regression model. Logistic regression analysis results are presented as odds ratio [95% confidence interval (CI); p-value]. Multiple linear regression was used to assess the association between calcified plaque proportion and depression. Calcified plaque proportion was the dependent variable and case-control status the independent variable of interest. A priori, sex, age, body mass index, hypertension, hyperlipidemia, and lifetime tobacco use were selected as potential confounders (diabetes and history of CAD were not applicable as covariates owing to their low frequency and absence in controls). The relation between calcified plaque proportion and prolonged use of antidepressants in the patients of the plaque composition cohort was assessed using the Spearman rank-order correlation. All tests were two-tailed and a significance level of 5% was utilized. Analyses were conducted using IBM SPSS Statistics version 20.0.0.1 (IBM Corporation, Armonk, New York, NY). RESULTS A total of 59 subjects were included in the study. One patient was excluded owing to alcohol dependence, 2 owing to absenteeism, and technical issues prevented processing of CT data from 1 patient leaving a total study population of 28 patients and 27 controls. Of the 28 patients, 6 met the criteria for moderate and 22 for severe depression. The median [interquartile range; range] duration of depressive episodes was 24 [10–41; 4–180] months (for cases with recurrent depression [n ¼ 2], the summed durations of all depressive episodes were used). Baseline characteristics for the total study population are displayed in Table 1. Seven patients and 7 controls had a total plaque volume of zero and, thus, were not included in the plaque composition cohort. The proportion of subjects with a total plaque volume of zero was not significantly different between patients and controls, 30% vs. 26%, p 4 0.99. Baseline characteristics in the plaque composition cohort (results not shown) resembled that of the total study population. However, in the plaque composition cohort, mean ⫾ standard deviation body mass index Psychosomatics 55:3, May/June 2014
Devantier et al. TABLE 1.
Baseline Characteristics
Variable Demographics Male sex, count (%) Age, y Education, y Cardiovascular risk factors History of CAD, count (%) Smoking, pack-y, median [IQR; range] Body mass index (kg/m2) Diabetes mellitus, count (%) Hypertension, count (%) Hyperlipidemia, count (%) Peripheral arterial disease, count (%) Left ventricular ejection fraction (%) Creatinine (mg/dl) AD treatment 4 6 months, count (%) Alcohol use, AUDIT score
Controls (n ¼ 27)
Patients (n ¼ 28)
p-Value
14 (52) 59.5 ⫾ 5.0 15.3 ⫾ 2.1
15 (54) 59.9 ⫾ 4.6 14.6 ⫾ 2.6
4 0.99 0.75 0.26
0 (0) 7.3 [0.5–15; 0–49] 25 ⫾ 2.8 0 (0) 12 (44) 20 (74) 0 (0) 59 ⫾ 2.2 0.8 ⫾ 0.2 0 (0) 6.0 ⫾ 3.5
3 (11) 19 [0–31; 0–80] 27 ⫾ 3.8 1 (3.6) 15 (54) 25 (89) 1 (3.6) 58 ⫾ 4.0 0.9 ⫾ 0.2 20 (71) 5.1 ⫾ 4.0
0.24 0.13 0.10 4 0.99 0.59 0.18 4 0.99 0.22 0.091 o 0.001 0.37
Data are presented as mean ⫾ standard deviation unless otherwise specified. All p values are two-tailed and p values o0.05 are displayed with bold. AD ¼ antidepressant; AUDIT ¼ Alcohol Use Disorder Identification Test; CAD ¼ coronary artery disease; IQR ¼ interquartile range.
was higher in patients than in controls, 26.7 ⫾ 4.1 vs. 24.4 ⫾ 2.2 kg/m2, respectively, p ¼ 0.034. Coronary CT Angiography Intravenous β-blockers were administered to 67% of the participants (71% in patients vs. 63% in controls, p ¼ 0.573), resulting in a mean ⫾ standard deviation heart rate during the CT scan of 61 ⫾ 11 beats per minute (range, 45–95 beats per minute). Estimated mean ⫾ standard deviation radiation dose was 3.2 ⫾ 2.0 mSv.
[0–69; 0–418], respectively, p ¼ 0.084. In the plaque composition cohort, the median [interquartile range; range] Agatston score was significantly higher in the patients, 92 [15–321; 0–1710] vs. 45 [0–101; 0–418], p ¼ 0.031. In the total study population, the higher values for total, calcified, and noncalcified plaque volume in patients as compared with controls did not reach statistical significance (Table 2). Moreover, late-onset major depression was not significantly associated with total coronary plaque volume in the unadjusted and adjusted logistic regression analysis, odds ratio ¼ 1.001 [95% CI: 0.999–1.003; p ¼ 0.25] and odds ratio ¼ 1.001 [95% CI: 0.999–1.003; p ¼ 0.23], respectively.
Coronary Plaque Burden There was a trend toward a higher median [interquartile range; range] Agatston score in patients compared with controls, 55 [0–262; 0–1710] vs. 14 TABLE 2.
Coronary Plaque Composition In the plaque composition cohort, the median calcified plaque proportion was twice as high in
Distributions of Coronary Plaque Measures
Variable 3
CP volume (mm ) NCP volume (mm3) Total plaque volume (mm3) CP–proportion (%)*
Controls (n ¼ 27)
Patients (n ¼ 28)
p-Value
3 92 92 7
16 136 172 14
0.15 0.62 0.48 0.044
[0–25; 0–109] [0–385; 0–949] [0–401; 0–1058] [3–14; 0–43]
[0–51; 0–769] [1–394; 0–1108] [2–454; 0–1620] [7–23; 0–47]
Data are reported as median [interquartile range; range]. All p values are two-tailed and p values o0.05 are displayed with bold. CP ¼ calcified plaque; NCP ¼ noncalcified plaque. n
Obtainable only in subjects with any plaque present (the plaque composition cohort), n ¼ 41.
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Coronary Plaque Volume and Composition TABLE 3.
Multiple Linear Regression Assessing the Association Between Coronary Plaque Composition and Late-Onset Major Depression
Independent variables
B
95% CI
p-Value
Model 1 Depression vs. no depression 7.14 0.23–14.5 0.057 Model 2: Model 1 þ sex and age Depression vs. no depression 7.04 0.53–14.6 0.067 Model 3: Model 2 þ BMI, hypertension, hyperlipidemia, and lifetime tobacco use Depression vs. no depression 11.3 2.63–20.1 0.012 Dependent variable is the calcified plaque proportion, %. All p values are two-sided and p values o0.05 are displayed with bold. B ¼ unstandardized regression coefficient; BMI ¼ body mass index.
patients compared with controls (Table 2). Multiple linear regression results are presented in Table 3. Unadjusted comparison of cases and controls showed a trend toward a significant association between late-onset major depression and calcified plaque proportion. After adjustments for demographics and cardiovascular risk factors, however, depression was significantly associated with a higher calcified plaque proportion. It is noteworthy that calcified plaque proportion was not correlated with age, n ¼ 41; r ¼ 0.11; 95% CI: 0.21 to 0.40; p ¼ 0.50, or prolonged use of antidepressants (patients only), n ¼ 21; r ¼ 0.00; 95% CI: 0.43 to 0.43; p 4 0.99. DISCUSSION In this study, the calcified, noncalcified, and total coronary plaque volumes were higher in patients with late-onset major depression compared with nondepressed controls, but the differences between groups did not reach statistical significance. However, the calcified to the total plaque volume ratio was twice as high in the patients (14% vs. 7%; p ¼ 0.044) indicating a difference in plaque composition between groups. Accordingly, having depression was associated with an increased calcified plaque proportion of 11.3 [95% CI: 2.63–20.1; p ¼ 0.012] percentage points after adjustment for demographics and cardiovascular risk factors. To the best of our knowledge, the present study is the first to use coronary CT angiography to assess the relation between depression and coronary plaque. The 248
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hitherto largest non–contrast enhanced CT study found no association between depression and Agatston score in 6814 middle-aged to elderly men and women.20 The 2 largest prospective studies show conflicting results: Stewart et al.17 found depression to increase the odds of incident coronary calcification by 61% in 2171 middle-aged men and women, whereas Newson et al.24 found no association in 1792 older adults. Overall, roughly half of the non–contrast enhanced CT studies available have found coronary calcification to be associated with depression,9–17 whereas the other half has not.18–26 We found a significant difference in the coronary plaque composition between patients and controls despite fairly similar plaque volumes. This study thus indicates that investigating plaque quantities alone cannot preclude a modulating effect of depression on plaque formation. This may be clinically relevant because plaque rupture risk depends more on plaque composition than on the size of a plaque.35 In this study, the calcified plaque proportion was twice as high in patients than in controls. Vascular calcification was previously thought to be a passive accumulation of calcium and phosphate, but now appears to be a regulated process involving induction of osteogenesis and reduced inhibition of mineralization.36 It is generally recognized that lipid deposits destabilize plaques, but the role of plaque calcification is less evident. In an in vitro stress test study of 20 human coronary lesions, Huang et al.37 found no destabilizing effect of calcifications on plaques but, concurrently, state that calcifications may still induce plaque defects in vivo. A destabilizing effect of calcifications on plaques in vivo is supported by Ehara et al.38 finding that a pattern of spotty calcification is more frequent in acute myocardial infarction than in stable and unstable angina pectoris. Another study has shown that calcification is negatively correlated with the degree of plaque macrophage infiltration, a factor associated with atherosclerosis and plaque instability.39 Paradoxically, the latter study also found a positive association between calcification and the relative size of the plaque lipid core.39 Altogether, the available data suggest that plaque calcification is a dynamic process that may influence plaque stability. Our finding of increased calcified plaque proportion in patients with late-onset depression thus seems important to promote the understanding of CAD in depression. Psychosomatics 55:3, May/June 2014
Devantier et al. The use of calcified plaque proportion for assessment of coronary plaque composition is, to the best of our knowledge, unprecedented. Consequently, studies are needed to understand how the calcified plaque proportion relates to clinical CAD. Therefore, the implications of the present study are primarily methodologic rather than clinical. Nonetheless, the present results urge health professionals to carefully consider CAD and to advocate reductions of lifestyle-related cardiovascular risk factors when treating depressed patients, especially patients with late-onset major depression. Methodologic Considerations The study cohort was small. Although not statistically significant, the median total plaque volume was notably higher in patients when compared with controls (172 mm3 vs. 92 mm3), and thus it may be speculated that the lack of statistical significance in plaque volume analyses represents a type II error. Therefore, larger studies investigating calcified and noncalcified plaque volumes in depressed patients are needed. The patients in the present study represented the severe end of the depression spectrum as all patients were either moderately or severely depressed, and most were hospitalized because of depression. Therefore, the results of this study may not be generalizable to most depressed patients. The long disease durations and thorough observation during hospitalization, however, contribute to an increased validity of the depression diagnoses. The study size precluded categorization of patients into subgroups based on depression duration and severity, characteristics that are likely to affect the interaction between depression and plaque formation and therefore should be considered in future studies. Antidepressant medication may affect plaque formation. The study design precluded comprehensive analyses of the effect of antidepressants on plaque composition, but the lack of
correlation between calcified plaque proportion and prolonged use of antidepressants does dispute that such an effect would be substantial. Finally, stratification of plaque into calcified or noncalcified plaque is crude when compared with histopathologic classification schemes. The presence or absence of calcium in a plaque does nonetheless reflect a difference in the plaque morphology.40 Furthermore, coronary CT angiography has limitations when differentiating between plaque components (e.g., lipid-rich and fibrotic components).27 A superior per plaque analysis could be performed in vivo using intravascular ultrasound, but, as opposed to CT angiography, intravascular ultrasound is an invasive and time-consuming procedure not suitable for examining the complete coronary artery tree.
Conclusion Although the coronary plaque burden was comparable in patients and in controls, late-onset major depression was associated with an increased calcified plaque proportion, reflecting a difference in the coronary plaque composition between groups. Future studies should evaluate the plaque composition, in addition to the plaque burden, when investigating coronary plaque in relation to depression, and health professionals should consider CAD when treating depressed patients. Disclosure: Cedars-Sinai Medical Center (Los Angeles, CA) may receive royalties for the licensing of the AutoPlaq software, a minority of which may be distributed to Damini Dey. All other authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. This work was funded by Aarhus University, the Central Denmark Region, the Danish Ministry of Science, Technology, and Innovation, and Augustinus Fonden, Denmark.
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