The non-negligible association between SYNTAX score and anxiety–depressive disorders

Summary

Objective

Anxiety–depressive disorders are more common in patients with coronary artery disease (CAD) and are strongly associated with higher morbidity and mortality rates. The Hospital Anxiety and Depression Scale (HADS) is a well-validated diagnostic tool for screening of anxiety–depression disorders. The SYNTAX score (SS) is the angiographic scoring system and is commonly used to evaluate the severity and complexity of CAD. The aim of this study was to evaluate the association between the HADS and SS.

Methods

The HADS questionnaire was filled in by subjects before the coronary angiography procedure. Biochemical, clinical and echocardiographic parameters, and SS were evaluated in all patients. Patients were assessed using the HADS. The patients were divided into two groups according to the SS [≥ 23: high SYNTAX score group (HSSG), < 23 low].

Results

The HADS scale was significantly higher in HSSG (24.8 ± 10.7 vs 11.3 ± 6.4 p < 0.001). There was no significant difference between the groups regarding laboratory parameters. On multivariate analysis, diabetes mellitus, hyperlipidaemia, and the HADS were independent predictors of high SYNTAX score.

Conclusion

In our study, we found that diabetes mellitus, hyperlipidaemia, and the HADS were independent predictors of a higher SS.

Anxiety–depressive disorders are common in patients with coronary artery disease (CAD), with an estimated prevalence of about 20–45%. Patients with CAD had a three-fold higher prevalence of major depressive disorder (MDD) than in the general population. Anxiety disorders are strongly associated with a lower quality of life, poorer somatic outcomes, higher medical costs, increased risk for all-cause mortality and major adverse cardiac events, independent of disease severity. Depression is associated with a 2.7-fold risk of impaired cardiovascular outcome and prognosis, independent of other risk factors in the post-myocardial infarction period.¹

The prevalence of minor or major depression is approximately 30–40% among patients undergoing coronary artery bypass graft surgery (CABG), and 15% of patients meet the full MDD criteria. The female gender, living alone, younger age, lower educational status and pre-CABG depressive symptoms are strongly associated with post-CABG depression.

Depression has been associated with longer hospitalisation, poorer functional outcomes, more peri-operative complications, worse health-related quality of life, progression of atherosclerotic disease, higher rates of rehospitalisation and mortality in patients undergoing CABG.² The American Heart Association has recommended routine screening for depression in CAD patients due to the unfavourable short- and long-term effects of depression on cardiovascular outcomes.³

The link between depression and CAD is most likely multifactorial. Some mechanisms have been proposed about the potential link between depression and CAD, including platelet hyper-reactivity (elevated plasma platelet factor 4 and β-thromboglobulin), endothelial dysfunction, inflammatory activation (increased C-reactive protein, interleukin-6, intercellular adhesion molecule-1 and fibrinogen levels), increased sympathetic activity and/or reduced vagal activity (reduced heart rate variability) and hypothalamic–pituitary– adrenal axis dysfunction.⁴ Additionally, behavioural and social characteristics of depressed patients, including unhealthy diet, sedentary lifestyle, insufficient medication adherence, tobacco use and chronic life stress might also contribute to the development and progression of CAD.⁵

The Hospital Anxiety and Depression Scale (HADS) has well-established psychometric features for the screening of depressive disorders and evaluation of the severity of depressive symptoms at different stages of CAD.⁶ Recently, Frasure-Smith et al.⁴ demonstrated that the HADS had acceptable sensitivity and specificity for screening of generalised anxiety disorder in stable CAD patients.

The SYNTAX score (SS) is an angiographic grading tool to evaluate the complexity and extensity of CAD. It is widely used for determining the optimal revascularisation strategy. It is also a powerful stratification mechanism allowing uniform, standardised assessment of CAD complexity and extensity.⁷

There is inconsistent data about the association between CAD and anxiety–depressive disorders in the literature. There are scarce data about the association between the HADS and SS. In the light of this, we assessed the relationship between the HADS and SS in this study population.

Methods

This prospective study involved 997 patients who had coronary angiography to investigate stable angina pectoris. We enrolled 244 subjects who were recommended CABG surgery after coronary angiographic evaluation in this study. The HADS questionnaire was filled in by subjects before the coronary angiography procedure.

The study was prospectively conducted according to the Declaration of Helsinki ethical principles for medical research involving human subjects. Informed consent was obtained from all patients who participated in this study, which was approved by the local ethics committee (YDU/2018/61-629).

Fasting venous blood samples were obtained from all patients following a fasting period of eight hours, to determine laboratory parameters. Patients with diabetes mellitus (DM) were identified on admission as those with documented DM using either oral hypoglycaemic agents or insulin treatment. Hypertension (HT) was defined as blood pressure above 140/90 mmHg or using antihypertensive therapy on admission. Hyperlipidaemia (HL) was defined as total cholesterol level at least 200 mg/dl (5.18 mmol/l) or using antihyperlipidaemic therapy on admission. Heart failure diagnosis was based on clinical features and echocardiography results. Patients with clinical features of heart failure or whose left ventricular ejection fraction was < 50% were excluded from the study. Chronic kidney disease was defined as a serum creatinine level > 1.5 mg/dl.

Patients with chronic liver disease, chronic kidney disease, inflammatory diseases and acute coronary syndromes were excluded. If the patients were taking anti-depressant therapy they were excluded. Thirty-five patients were excluded and a total of 209 patients were included in our study. The data of patients were prospectively analysed for demographic features, echocardiographic parameters, biochemical parameters, HADS and SS.

All patients underwent transthoracic echocardiography using a Vivid S5 (GE healthcare) echocardiography device and Mass S5 probe (2–4 MHz). Standard two-dimensional and colour-flow Doppler views were acquired according to the guidelines of the American Society of Echocardiography and European Society of Echocardiography.⁸ The ejection fraction was measured according to Simpson’s method.

All patients underwent elective coronary angiography according to the Judkins technique. Angiograms were reviewed by at least two non-blinded reviewing cardiologists.

All lesions causing ≥ 50% stenosis in a coronary artery with a diameter ≥ 1.5 mm were included in the SS calculation. Website software (http://www. SYNTAXcore.com) was used for the calculation. Scoring was performed for each patient in keeping with the following parameters: coronary dominance, number of lesions, segments included per lesion, the presence of total occlusion, bifurcation, trifurcation, aorto-osteal lesion, severe tortuosity, calcification, thrombus, diffuse/small-vessel disease and lesion length > 20 mm. The SS was evaluated separately by two interventional cardiologists blinded to the study protocol and patient characteristics. Patients were divided into two groups according to the SS: ≥ 23, high, < 23, low.

The anxiety–depression status of our study population was evaluated using the HADS questionnaire. This questionnaire is a routine diagnostic tool for the evaluation of anxiety–depressive disorders in different countries.⁹ It has two subscales, including anxiety and depression, each of which comprised items rated on a four-point Likert scale. The total HADS score ranged between 0 and 42 with 0–14 being considered low, 15–28 moderate and 29–42 high. This questionnaire has previously been well validated to assess anxiety and depression in patients with CAD.¹⁰

Statistical analysis

Statistical analysis was performed using the SPSS (version 20.0, SPSS Inc, Chicago, Illinois) software package. Continuous variables are expressed as the mean ± standard deviation (SD), and categorical variables are expressed as a percentage. The Kolmogorov–Smirnov test was used to evaluate the distribution of variables. The Student’s t-test was used to evaluate continuous variables showing normal distribution, and the Mann–Whitney U-test was used to evaluate variables that did not show a normal distribution. A p-value < 0.05 was considered statistically significant.

To identify the predictors of higher SS, the following variables were initially assessed in a univariate model: DM, HL, smoking and HADS. Significant variables in univariate analysis were then entered into a multivariate logistic regression analysis using backward stepwise selection. Furthermore, receiver operating characteristic (ROC) curve analysis was applied to evaluate the diagnostic performance of HADS for differentiating between low and high SS patients.

Results

The high SYNTAX score (HSS) group had a higher prevalence of DM, HL and smoking (60.3 vs 31.7%, p < 0.001; 66.4 vs 29.1%, p < 0.001; 57.3 vs 34.7%, p < 0.001, respectively) (Table 1). There was no significant difference between the groups with regard to age, gender, marital status, body mass index, educational level and medication (Table 1). The HADS was significantly higher in the HSS group (24.8 ± 10.7 vs 11.3 ± 6.4, p < 0.001) (Table 1). There was no significant difference between the two groups with regard to laboratory parameters or left ventricular ejection fraction (64.3 ± 6.1 vs 64.7 ± 5.9%, p = 0.739) (Table 2).

Table 1. Patient characteristics.

	SS 23	SS<23
Patient characteristics	(n = 124)	(n = 85)	p-value
Age (years), mean + SD	67.4 + 9.5	64.9 + 11.5	0.687
Female gender, %	36.9	34.6	0.672
Marital status, %
Single	21.9	22.7	0.861
Married	54.6	55.3	0.637
Divorced	23.5	22.0	0.539
Body mass index (kg/m²)	26.1	24.9	0.738
Hypertension, %	73.9	71.4	0.867
Diabetes mellitus, %	60.3	31.7	<0.001
Hyperlipidaemia, %	66.4	29.1	<0.001
Smoking, %	57.3	34.7	< 0.001
Educational level, %
Primary school	27.6	28.3	0.659
Secondary school	58.3	57.4	0.851
Tertiary education	14.1	14.3	0.962
ACEI/ARB therapy, %	56.7	54.9	0.736
Beta-blocker therapy, %	49.5	50.7	0.761
Statin therapy, %	58.3	59.1	0.738
Aspirin therapy, %	81.3	80.8	0.783
HADS, mean + SD	24.8 + 10.7	11.3 + 6.4	< 0.001

ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; HADS: hospital anxiety and depression scale.

Table 2. Laboratory and echocardiographic parameters of the study population.

Laboratory parameters	SS 23 (n = 124), mean + SD	SS<23 (n = 85), mean + SD	p-value
Haemoglobin (g/dl)	13.9 + 3.1 (14.3)	14.3 + 2.9 (14.5)	0.621
Platelets (X 10 superscript(3) cells/ul)	314.7 + 74.3 (346.5)	309.6 + 69.4 (339.1)	0.534
White blood cells 103 cells/ul)	8.3 + 4.7 (9.3)	7.8 + 3.7 (9.1)	0.639
Creatinine (mg/dl)	0.79 + 0.27(0.83)	0.67 + 0.31 (0.78)	0.427
Fasting plasma glucose (mg/dl)	87.1 + 23.8 (96.3)	83.4 + 26.7 (92.8)	0.382
[mmol/l]	[4.83 + 1.32 (5.34)]	[4.63 + 1.48 (5.15)]
C-reactive protein (mg/dl)	1.39 + 0.73 (1.57)	1.27 + 0.83 (1.49)	0.561
Total cholesterol (mg/dl) [mmol/l]	204.7 + 64.9 (237.3) [5.30 + 1.68 (6.15)]	194.6 + 54.3 (231.4) [5.04 + 1.41 (5.99)]	0.493
High-density lipoprotein cholesterol (mg/dl)	31.6 + 11.8 (36.7)	34.3 + 10.9 (38.5)	0.637
[mmol/l]	[0.82 + 0.31 (0.95)]	[0.89 + 0.28 (1.00)]
Low-density lipoprotein cholesterol (mg/dl)	176.3 46.7 (194.8)	169.7 + 51.9 (188.7)	0.472
[mmol/l]	[4.57 + 1.21 (5.05)]	[4.40 + 1.34 (4.89)]
Trigylicerides (mg/dl) [mmol/l]	183.6 + 49.7 (196.5) [2.07 + 0.56 (2.22)]	178.5 + 51.7 (188.3) [2.02 + 0.58 (2.13)]	0.381
TSH (mIU/ml)	3.4 + 1.3 (3.8)	3.2 + 1.1 (3.7)	0.847
Uric acid (mg/dl)	7.1 + 3.4 (9.4)	7.0 + 3.2 (9.6)	0.861
Left ventricular ejection fraction (%)	64.3 + 6.1 (65.4)	64.7 + 5.9 (65.9)	0.739

TSH: thyroid-stimulating hormone.

On multivariate analysis DM, HL and the HADS were independent predictors of HSS [odds ratio (OR): 3.164; 95% confidence interval (CI): 1.937–6.934, p < 0.001; OR: 3.429, 95% CI: 1.861–7.657, p < 0.001; OR: 2.736, 95% CI: 1.934–4.092, p < 0.001, respectively] (Table 3). In ROC analysis, a cut-off value was determined for the HADS with high SS. The cut-off value was 21.4 [area under the curve (AUC) = 0.668; 80.9% sensitivity, 69.9% specificity, 95% CI: 0.583–0.753] (Fig. 1).

Table 3. Laboratory and echocardiographic parameters of the study population.

Predictor variables	OR (95% CI)	p-value
Diabetes mellitus	3.164 (1.937-6.934)	< 0.001
Hyperlipidaemia	3.429 (1.861-7.657)	< 0.001
HADS	2.736 (1.934-4.092)	< 0.001

Fig. 1.

ROC curve analysis to evaluate the diagnostic performance of the HADS for differentiating low and high SS patients.

Discussion

In our study, we found that DM, HL and HADS were independent predictors for a higher SS. Besides, DM and HL are major risk factors for the development of CAD. Changes in lipid and carbohydrate metabolism accompanying insulin resistance lead to the appearance of atherogenic lipoproteins, hyperglycaemia and increased concentration of free fatty acids. Several studies found that DM and HL were strongly associated with extensity and complexity of CAD.¹¹ Tanaka et al.¹² found that age, male gender and DM were significant and independent risk factors for a higher SS.

Anxiety–depressive disorders are common in patients with CAD and are consistently associated with lower quality of life, higher medical cost, poorer somatic outcomes and mortality.

Approximately half of the patients with CAD suffer from depressive symptoms and 20% of patients with CAD meet the criteria for MDD.¹ Among patients undergoing CABG surgery, approximately 30–40% of patients meet the criteria for minor or major depression, with roughly 15% of patients meeting full MDD criteria.²

Inflammatory cytokines [C-reactive protein (CRP) and interleukin-6 (IL-6)] have been strongly associated with atherosclerotic plaque-related adverse events. Depression also has been linked to increased levels of cytokines (CRP, IL-1, IL-6), and also depression can predict cardiovascular mortality.¹³

Two possible mechanisms have been proposed to clarify the association between inflammation, depression and cardiovascular disease. First, reduced serotonin action in the medial prefrontal cortex might be associated with increased inflammatory cytokines. Second, increased levels of interferongamma is associated with elevated activity of an enzyme that degrades tryptophan (a serotonin precursor) to kynurenine in patients with CAD.¹⁴ Lower levels of serotonin may be another mechanism of the connection between inflammation and depression in patients with cardiac disease.¹⁵

Endothelial dysfunction has been associated with the development of ischaemic CAD in patients with atherosclerosis. While a normal endothelium typically releases nitric oxide (NO) in response to serotonin to ensure adequate blood flow through the coronary arteries, in atherosclerotic segments it fails. This results in vasoconstriction in the atherosclerotic segments and may lead to myocardial ischaemia and coronary thrombosis.¹⁶

Inflammation is associated with CAD, and it also impairs endothelial NO release. Depression has also been associated with impaired endothelial function in patients with or without CAD.¹⁷ Selective serotonin re-uptake inhibitor (SSRI) treatment has led to improved endothelial function in patients with depression and CAD.¹⁸ Platelet activation, adhesion and aggregation are important components of cardiovascular disease, and increased platelet activity is strongly associated with adverse cardiovascular events. Serotonin plays a key role in platelet biology through its binding with 5-hydroxytryptamine (5-HT) receptors on the platelets. In atherosclerotic arteries, serotonin leads to platelet aggregation.¹⁶ Furthermore, elevated levels of blood serotonin predict CAD and future ischaemic cardiac events in patients with suspected CAD. SSRIs consume platelet serotonin stores by inhibiting platelet uptake of serotonin, and are also associated with decreasing platelet aggregation in patients with CAD.¹⁹

Heart rate variability (HRV) is a well-known risk factor for adverse cardiovascular outcomes. Depressed patients have linearly reduced HRV associated with the severity of depression. Furthermore, patients with both CAD and depression have greater decreases in HRV.²⁰

In addition to the abovementioned mechanisms, brain-derived neurotrophic factor (BDNF) may also play an important role in the association between depression and adverse cardiovascular events. Depression has been strongly and consistently linked to low levels of BDNF, which were linked to increased cardiomyocyte death and impaired systolic function in experimentally induced myocardial infarction.²¹

Medication non-adherence and lower level of physical fitness are associated with an increased risk of cardiovascular events in patients with MDD. Depressed patients fail to succeed in healthpromoting behaviours, including maintenance of a healthy diet, regular exercise, adherence to medications, stress reduction and lowering of cholesterol level.⁵

There are inconsistent results about the association between anxiety–depression and CAD in the literature. Low et al.²² found an inverse association between coronary artery occlusion and anxiety symptoms. Assari et al.²³ found an inverse association may exist between the extent of coronary stenosis (single-, two-, threevessel disease) and the severity of anxiety symptoms in patients who undergo coronary angiography.

On the other hand, Tennant and et al.²⁴ found no association between angiographic findings and psychological status, including anxiety levels. Additionally, Vural et al.²⁵ found that the depression score was strongly correlated to CAD after controlling for gender and other variables. They reported that every five-point increase in depression score was associated with a 25–30% increase in the risk of abnormal coronary angiography findings or definitive CAD.

In the literature, different severity modalities were used to evaluate the extensity/severity of CAD.^24,25 In our study, the SS system was used with high diagnostic value to evaluate the extensity and severity of CAD, and a higher anxiety–depressive scale was found to be an independent predictor of high SS.

Although adverse cardiovascular outcomes of anxiety– depressive disorders are well known, healthcare providers often fail to identify obvious symptoms of anxiety in patients with CAD. Considering the close association between MDD and adverse cardiovascular outcomes, every patient should be evaluated with regard to anxiety–depressive disorders, according to the American Heart Association recommendation.³

Our study has some limitations. First is the small sample size of this study. Second, by nature of the cross-sectional study, we cannot claim a definitive causal relationship between CAD and anxiety–depression disorder. Third, we evaluated symptoms of anxiety–depression instead of the clinical diagnosis of any anxiety–depression disorder. Fourth, our results cannot be applied to patients with acute coronary syndromes because only stable CAD patients were involved in our study.

Conclusion

In our study, we found that DM, HL and HADS were independent predictors of a higher SS. Physicians should pay attention to the importance of anxiety–depressive disorder assessment, which is likely to be overlooked due to intensive daily routine programmes. Further studies with a larger number of patients are required for evaluation of the association between the severity of anxiety–depression and CAD.