Autonomic nervous system, inflammation and preclinical carotid atherosclerosis in depressed subjects with coronary risk factors

Transcription

1 Autonomic nervous system, inflammation and preclinical carotid atherosclerosis in depressed subjects with coronary risk factors Carmine Pizzi 1 ; Lamberto Manzoli 2, Stefano Mancini 3 ; Gigliola Bedetti 4 ; Fiorella Fontana 1 ; Grazia Maria Costa 5 1 Department of Internal Medicine, Aging and Nephrological Diseases, University of Bologna. 2 Section of Epidemiology and Public Health, University G. d Annunzio of Chieti, Italy; 3 Department of Internal Medicine, University of Modena and Reggio Emilia. 4 Division of Cardiology, S. Maria della Scaletta Hospital, Imola, Italy; 5 Department of Cardiovascular Disease, University of Bologna, Italy

2 Background The prevalence of depression in patients with coronary heart disease (CHD) is estimated to be about of 40%, and half of these patients develop major depression. Depression has appeared as a new and important cardiac risk factor and the occurrence of depression in patients with CHD leads to an unfavorable outcome. Recent evidence has suggested that a diagnosis of depression following myocardial infarction conferred a 2- to 2.5-fold increased independent risk of a poorer cardiovascular prognosis. In fact, a relationship between the symptoms of depression and the severity of CHD has been documented, suggesting that depression disorders could accelerate atherosclerosis progression and its clinical complications. However, the cause of accelerated atherosclerosis in patients with depression and CHD remains unclear

3 Background Detecting the early stage of atherosclerosis is of major clinical relevance because it may offer the possibility of identifying patients with increased cardiovascular disease morbidity and mortality. Intima media thickness (IMT), measured by ultrasound, represents a surrogate marker for subclinical atherosclerosis and has been documented as a marker of cardiovascular risk in subjects with or without CHD. Recent studies have demonstrated that depressed subjects exhibit greater IMT as compared to controls.

4 Aim of the Study The aim of the present study was to investigate the relationship between vascular atherosclerosis and depression in subjects at risk for CHD but free from disease. We therefore examined the possible associations between traditional and non-traditional risk factors for atherosclerosis and depression.

5 Methods Study Population Inclusion criteria werea negative exercise stress test result and the presence of selected CHD risk factors 2 (age 60 years, male gender, smoking, hypertension, dislipidemia, positive familiy history of CHD). Exclusion criteria were the presence of neoplasm, kidney or liver failure, systemic inflammatory disease, current antidepressant treatment, left bundle block, paced rhythm, Wolff Parkinson White syndrome or patho-physiological conditions which could alter the analysis of heart rate variability (HRV), diabetes mellitus, peripheral neuropathy, atrial fibrillation and an ejection fraction <45%. We also excluded subjects with IMT>1.5 mm because such values are indicative of plaque according to the joint European Society of Hypertension (ESH)/European Society of Cardiology guidelines. (Table 1).

6 Methods Assessment of depressive mood Depression was evaluated at baseline and the end of the study using the BDI, a 21-item self-reported measure of depressive symptoms, each answer being scored on a scale value of 0 to 3 (35). Scores ranged from 0 to 63. Higher total scores indicate more severe depressive symptoms. A score 10 was considered a valid indication of clinically significant depression. Measurement of carotid intima-media thickening: To measure early atherosclerosis, we used ultrasound of intima-media thickening (IMT) measurements of the far wall of the common carotid artery. Image acquisition included the evaluation of the right and left common carotid arteries, 1 cm proximal to the carotid bulb. The left and right far walls of the carotid artery segments were imaged in a standardized magnification (2 x 2 cm). The sonographer used different scanning angles to identify the maximum thickness of the IMT, 1 cm proximal to the carotid bulb. Intima-media thickness was defined for the common carotid artery as the mean of the maximum wall thicknesses for the near and far walls on the right and left common carotid segments

7 Methods Assessment Heart Rate Variability To measure altered cardiac autonomic tone, we used time-domain components of HRV in 24-h Holter recordings as previously described (16).The following parameters were considered in the analysis: standard deviation (SD) for the time between normal-tonormal complexes in the entire 24-h electrocardiographic recording (SDNN), SD of the average normal-to-normal intervals for each 5-min period (SDANN), root-mean square of differences of successive RR intervals (RMSSD) and the percentage of adjacent RR intervals >50 ms apart (pnn50). Under these conditions, SDNN, and SDANN are indices of both parasympathetic and sympathetic tone as mediated by baroreflex activity. RMSSD and pnn50 are measurements of the modulation of parasympathetic tone Biochemical measurements After 30 minutes of rest, venous blood was collected in EDTA and stored at -80 C until time of analysis. Fibrinogen (Clauss method), C-reactive protein (CRP, Latex/BN II, Dade Behring) and Interleukin 6 (IL-6, Quantikine human IL-6) were also measured.

8 Results As shown in Table 2, As shown in Table 2, the mean levels of most lipidic indices (total cholesterol, LDL-cholesterol, and triglycerides) were significantly higher in depressed as compared to non-depressed subjects. Similarly, obesity was more frequent in depressed individuals, although the mean BMI of two groups was comparable. The distribution of all other cardiovascular risk factors as well as medications were similar across the groups (Table 2). Compared with non-depressed subjects, those with depression had significantly higher median values of most inflammatory markers: IMT, CRP, IL-6, SDNN, SDANN and RMSSD (Table 3). Heart rate was similar across groups while the difference in pnn50 levels was only borderline significant.

9 Results The results of multivariate linear and logistic regression analyses investigating potential independent predictors of depression symptoms are reported in Tables 4 and 5, respectively. In logistic analysis, after adjustment for age, gender, smoking, systolic blood pressure, BMI, IL-6, CRP and SDANN, the inverse of the average IMT showed an odds ratio of 0.71 (95% Confidence Interval: ), indicating that depressed patients had significantly higher values of IMT as compared to non-depressed individuals. As regards the other predictors, total cholesterol and CRP levels were positively associated with depression (p<0.05 and p<0.001, respectively), whereas depressed subjects showed significantly lower levels of SDANN (10 unit increase was associated with an adjusted odds ratio of depression equal to 0.51; 95% CI: ). In linear regression, standardized coefficients indicated that the most important domains in predicting BDI scores were C-reactive protein levels (standardized coefficient = 0.436), SDANN (-0.230) and IMT inverse ( ).

10 TABLE 1. Flow of the participants (a total of 590 subjects were asked to participate) Reasons for exclusion N. of subjects Refusal to provide informed consent 56 Diabetes mellitus 53 Missing data on some items of the depression score 25 Current antidepressant treatment 21 Intima-media thickness >1.5 mm 18 Ejection fraction <45% 8 Coronary heart disease 7 Cancer detection 3 Kidney or liver failure 2 Systemic inflammatory disease 2 Atrial fibrillation 1 Left bundle block 1 Paced rhythm 1 Wolff Parkinson White syndrome 1 Overall 199

11 TABLE 2. General characteristics of the sample. Continuous variables (mean ± SD) Non-Depressed (n=301) Depressed (n=90) Age, y 57.8± ± BMI, kg/m ± ± Systolic Blood Pressure, mm Hg 143±21 145± Diastolic Blood Pressure, mm Hg 81±7 82±8 0.1 Total Cholesterol, mg/dl 207±23 216± HDL-Cholesterol, mg/dl 53±12 52±18 <0.001 LDL-Cholesterol, mg/dl 124±24 134± Triglycerides, mg/dl 137±30 145± Global fatal CHD risk at ten years 2.1± ± p *

12 Categorical variables, n (%) CHD risk factors Non-Depressed (n=301) Depressed (n=90) Male gender 156 (51.8) 45 (50.0) 0.4 Obesity (BMI 30) 25 (8.3) 30 (33.3) <0.001 Dyslipidemia 135 (44.6) 41 (45.6) 0.5 Hypertension 145 (61.7) 51 (50.0) 0.1 Current smoking 87 (28.9) 31 (34.4) 0.2 Family History 100 (33.2) 37 (41.1) 0.2 High-risk for fatal CHD (score>=5%) 33 (11.1) 14 (15.5) 0.3 Medications β-blockers 105 (34.9) 32 (35.6) 0.5 Calcium channel blockers 66 (21.3) 25 (27.8) 0.2 ACE-Inhibitors 91 (30.2) 33 (36.7) 0.2 Statins 76 (25.3) 25 (27.8) 0.4 Antiplatelet drugs 113 (37.5) 36 (40.0) 0.4 p

13 TABLE 3. Selected inflammatory markers, indices of endothelial function and heart rate variability by depression status. Inflammation Markers Non Depressed (BDI<10) n=301 Beck Depression Inventory (BDI) Depressed (BDI 10) n= 90 p Correlation with BDI score: Spearman p C-reactive protein, mg/dl <0.001 <0.001 ( 0.44) Interleukin-6, pg/ml < ( 0.22) Indices of Subclinical Atherosclerosis, mm IMT Intima-media thickness left <0.001 <0.001 ( 0.35) IMT Intima-media thickness right <0.001 <0.001 ( 0.32) IMT Intima-media thickness - average <0.001 <0.001 ( 0.34) Time-domain Measures of Heart Rate Variability Heart Rate, bpm ( 0.09) SDNN, ms <0.001 <0.001 ( 0.26) SDANN, ms <0.001 <0.001 ( 0.35) RMSSD, ms ( 0.12) Mean % of adjacent cycles>50 ms apart (pnn50)

14 TABLE 4. Results from the multivariable regression model evaluating the association between Beck Depression Inventory score (on a logarithmic scale) and various explanatory factors. Partially adjusted model * Fully adjusted model ** Regression coefficient Demographic and cardiovascular risk factors Robust SE p Regression coefficient Robust SE STD coefficient Age (1 year increase) Male gender BMI (1 point increase) Systolic Blood Pressure (1 mmhg increase) Total Cholesterol (10 mg/dl increase) < HDL-Cholesterol (1 mg/dl increase) Triglycerides (1 mg/dl increase) Current smoking Family History of CHD Global fatal CHD risk at ten years *** p

15 Inflammation Markers Partially adjusted model * Fully adjusted model ** Regression coefficient Robust SE p Regression coefficient Robust SE STD coefficient C-reactive protein, mg/dl < <0.001 Interleukin-6, pg/ml Indices of Subclinical Atherosclerosis Inverse of the average Intima-media thickness (0.1 mm increase) Time-domain Measures of Heart Rate Variability Heart Rate (1 bpm increase) SDNN (1 units increase) < <0.001 SDANN (10 units increase) < <0.001 RMSSD (1 ms increase) Mean % of adjacent cycles>50 ms apart (pnn50) (1% increase) p

16 Table 5. Results from logistic regression model predicting depression (Beck Depression Inventory score 10). Demographic and cardiovascular risk factors Partially adjusted model * Fully adjusted model ** OR (95% CI) p OR (95% CI) p Age (1 year increase) 0.99 ( ) ( ) 0.7 Male gender 0.98 ( ) ( ) 0.4 BMI (1 point increase) 1.04 ( ) ( ) 0.8 Systolic Blood Pressure (1 mmhg increase) 1.08 ( ) ( ) 0.12 Total Cholesterol (10 mg/dl increase) 1.30 ( ) < ( ) HDL-Cholesterol (1 mg/dl increase) 0.98 ( ) Triglycerides (1 mg/dl increase) 1.01 ( ) Current smoking 1.42 ( ) ( ) Family History of CHD 1.01 ( ) 0.9 Global fatal CHD risk at ten years *** 1.03 ( ) 0.5

17 Inflammation Markers Partially adjusted model * Fully adjusted model ** OR (95% CI) p OR (95% CI) p C-reactive protein, mg/dl 2.79 ( ) ( ) <0.001 Interleukin-6, pg/ml 1.66 ( ) ( ) Indices of Subclinical Atherosclerosis Inverse of average Intima-media thickness (0.1 mm increase) Time-domain Measures of Heart Rate Variability Heart Rate (1 bpm increase) 1.01 ( ) 0.4 SDNN (1 units increase) 1.02 ( ) ( ) < ( ) <0.001 SDANN (10 units increase) 0.48 ( ) < ( ) <0.001 RMSSD (1 ms increase) 0.97 ( ) 0.2 Mean % of adjacent cycles>50 ms apart (pnn50) (1% increase) 0.98 ( ) 0.7

18 Conclusions This large population-based study showed an independent association between depression and increased carotid IMT values. Such association remained highly significant after controlling for several potential confounders including age, gender, main cardiovascular risk factors and inflammatory markers. This study showed the presence of an independent association between an increased intima-media thickness and depression symptoms suggesting that the subclinical atherosclerosis found in depressed patients may be dependent on some of the patho-physiological mechanisms linking depression and coronary artery disease.

19 Legend * Two hierarchical regression analyses were carried out: the first model included only demographic and cardiovascular variables; the second model included only inflammatory markers. ** The final linear regression model included all significant variables and others forced to entry because of clinical relevance. All variables that have not been included in this model were non significant after adjustments. Parameters of the model: n. of obs. = 384; R-squared = *** According to the SCORE chart based on total cholesterol for populations at low cardiovascular disease risk. In order to avoid multicollinearity, this variable was included in a different separate hierarchical model including only those variables which are not included in SCORE computation (HDL-cholesterol, triglycerides, and family history of CHD). Standard deviation of the mean value of time between normal complexes. Standard deviation of the average of NN intervals for each 5 min. period. Index of the autonomic parasympathetic nervous system.