Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis
*Correspondence: DD Balci. E-mail: email@example.com
Psoriasis is a common chronic inflammatory skin disease characterized by erythematous plaques with silvery scale.1 The pathogenesis of psoriasis includes increased T lymphocyte activity with auto- or super-antigen presentation and keratinocyte hyperproliferation due to the release of cytokines and chemokines from activated T lymphocytes.2 Recent research has shown that chronic and systemic inflammation plays a major role in the development of atherosclerosis.3,4 Population-based studies have demonstrated an association between psoriasis and an increased risk of atherosclerosis. The comorbidities associated with psoriasis, such as smoking habits, obesity, hypertension, diabetes mellitus and hyperlipidemia, are all factors contributing to the development of atherosclerosis.5,6
Endothelial dysfunction is an early feature of atherosclerosis. The carotid artery intima-media thickness (IMT) and brachial artery vasodilatation response to physical and chemical stimuli are the best sonographic markers of early atherosclerotic changes. The carotid and brachial arteries are easily accessible to non-invasive examination using ultrasound techniques. High-resolution B-mode ultrasonography allows reliable measurement of the carotid artery IMT and brachial artery diameter. Brachial artery flow-mediated dilatation (FMD) has become a common ultrasonographic method for the non-invasive assessment of endothelial function.7–9 Measurements of carotid artery IMT and brachial artery FMD are widely used to evaluate premature atherosclerosis in chronic inflammatory diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).10–12 B-mode ultrasonographic measurement of the carotid artery IMT has highly reliable intra- and interobserver variability.13 However, there are conflicting data regarding the reliability of the IMT for evaluating premature atherosclerosis. It has been suggested that the carotid artery IMT does not always correlate with atherosclerosis, particularly in relatively young individuals with chronic inflammatory disease.11 Some recent studies have shown impaired endothelial function and increased carotid artery IMT in patients with psoriatic arthritis without cardiovascular risk factors.10–12
This study compared the subclinical atherosclerosis of the carotid and brachial arteries in psoriasis vulgaris patients and healthy controls using high-resolution ultrasonography.
Forty-three consecutive patients with psoriasis vulgaris attending our dermatology outpatient clinic and 43 sex- and age-matched healthy controls were included in this study. Informed consent was obtained from all participants, and the study protocol was approved by the ethics committee of our institution. Before conducting the study, a power analysis was performed based on the results of a pilot study (n = 20). With a sample size calculator (DSS Research, Fort Worth, TX), it was estimated that 37 subjects for each group were needed to give this study a power of 90% in showing a relevant change in flow-mediated dilatation with a 95% confidence interval (95% CI). As we anticipated an approximately 20% dropout rate, given that patients might be unwilling to be scanned, we included 86 patients in the study. The diagnosis of psoriasis vulgaris was based on a clinical or histopathological examination of all patients. Controls were recruited from the academic or peripheral staff of our hospital and their healthy relatives. Diabetes mellitus (fasting overnight venous plasma concentration > 110 mg/dL), hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg), a history of cardiovascular or cerebrovascular disease, renal failure (serum creatinine values > 1.3 mg/dL) and age younger than 18 years were exclusion criteria. Subjects who were receiving lipid-lowering therapy, antihypertensive or anti-aggregant drugs, nitrates, or long-term systemic steroids were also excluded. The duration of the disease, medication and smoking habits of the patients were recorded. Subjects who reported smoking at least one cigarette per day during the last year were classified as smokers, whereas those who had stopped smoking at least 5 years previously were deemed non-smokers. The disease severity was quantified using the Psoriasis Area and Severity Index (PASI). The morning after an overnight fast, blood samples were obtained for total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), glucose and creatinine in all subjects. The waist hip ratio (WHR) was calculated as the ratio of the waist and hip circumferences. Body mass index (BMI) was calculated as the ratio of weight (kg) to height (m) squared (kg/m2).
All subjects were examined using a high-resolution Doppler ultrasound (Acuson Antares 5.0, Siemens Medical Solutions, Mountain View, CA) using a 13–5 MHz linear array transducer in the supine position. All ultrasonographic measurements were obtained by a single radiologist. All images of the brachial and carotid arteries were recorded on the hard disk of the ultrasound system for subsequent analysis and evaluated by two independent investigators who were unaware of the subjects’ clinical status. At least three cardiac cycles of each measurement were recorded to account for intraobserver variation, and the mean values were expressed. The subjects had fasted overnight and they were studied in the morning between 8 and 12 AM.
Brachial artery study
The nitroglycerin-induced dilatation (NTD) and FMD of the brachial artery were measured as described previously.9,14 The right brachial artery was examined in all subjects. The brachial artery diameter (BAD) was measured at the onset of the QRS complex on the ECG, which was monitored throughout the scans. After the subjects had lain at rest in the supine position for 10 min in a temperature-controlled room (20–25 °C), a longitudinal section of the right brachial artery was scanned approximately 2 to 5 cm above the antecubital fossa for baseline measurements. After optimal transducer positioning, the skin was marked for reference for later measurements. Subsequently, the blood pressure cuff placed around the arm above the scanned part of the artery was inflated to a pressure of 220 mmHg. After 5 min, the cuff was deflated. The arterial diameter was measured 45–60 s after cuff deflation. After a 10-min rest, a single dose of nitroglycerin (NTG) 0.4 mg was administered sublingually, and 5 min later, the measurements for calculating the FMD were obtained. FMD was calculated as the percent increase in arterial diameter during reactive hyperaemia vs. the corresponding rest value (FMD% =[(BAD after cuff deflation – baseline BAD)/(baseline BAD)] × 100). The brachial artery diameter was measured after NTG was administered and the NTG-induced dilatation was calculated as the percent increase in arterial diameter after NTG vs. the corresponding rest value (NTD% = [(BAD after NTG – baseline BAD)/(baseline BAD)] × 100).
Carotid artery study
The bilateral common carotid arteries (CCA), internal carotid arteries (ICA) and external carotid arteries (ECA) were scanned carefully and any focal lesion in the intima larger than 1.5 mm was described as an atherosclerotic plaque. The bilateral CCAs were scanned longitudinally to measure the IMT. Images were obtained from the distal portion of the common carotid artery, 1 to 2 cm proximal to the carotid bulb. The two bright echogenic lines in the arterial wall were identified as the intima and media lines. The IMT was measured as the distance from the main edge of the lumen-intima interface of the media-adventitia interface of the CCA. The intra and interobserver variability had coefficient of variations of less than 1% for the measurements of IMT, FMD and NTD.
Continuous data are expressed as the mean ± standard deviation (SD), and categorical variables are expressed as percentages. Patients and control subjects were compared using Student's t-test for continuous variables and the chi-squared test for categorical variables. Subgroup analyses for continuous variables were also performed using Student's t-test.
An analysis of covariance, adjusted by the HDL levels, was used to compare the subclinical atherosclerosis indicators in patients and control subjects. The Mann-Whitney U-test was used to determine the association between therapy and the subclinical atherosclerosis indicators (carotid artery IMT and brachial artery FMD and NTD).
Multiple linear regression analyses were used to assess independent associations between the subclinical atherosclerosis indicators and other variables. An enter model was used in all the multiple linear regression analyses. The variables significantly associated with each of the subclinical atherosclerosis indicators (P < 0.05) in the Pearson correlation analysis were included as independent variables in the multiple linear regression analysis models. Two-sided P-values of less than 0.05 were considered statistically significant. The statistical analysis was carried out using the Statistical Package for the Social Sciences (SPSS) version 15 (SPSS, Chicago, IL).
Clinical characteristics of the study subjects
The main demographic, clinical and laboratory features of the subjects are shown in Table 1. The two groups were similar with respect to the variables age, sex, BMI, WHR, smoking status, total cholesterol, LDL cholesterol and TG levels. However, the mean HDL cholesterol value of the psoriasis patients was significantly lower, compared with the controls (P = 0.01). A total of 52 consecutive patients with psoriasis were admitted. Nine patients were excluded from the study, including two patients with DM, two with hypertension, two younger than 18 years, one with a past cardiovascular event, one who was receiving lipid-lowering therapy, and one who was receiving long-term systemic steroids. The remaining 43 patients were included.
Table 1. Demographic, clinical and laboratory features of the subjects
|Age (year)|| 38.47 ± 14.36|| 38.07 ± 13.88||0.897|
|Male/female (number)|| 23/20|| 23/20||1.0|
|Disease duration (year)|| 13.26 ± 10.55|| || |
|PASI|| 6.50 ± 4.44|| || |
|BMI (kg/m2)|| 26.31 ± 4.72|| 25.25 ± 3.82||0.257|
|WHR (%)|| 87.21 ± 9.12|| 85.28 ± 7.15||0.278|
|Smoking (number)|| 9|| 8||0.787|
|Total cholesterol (mg/dL)||182.91 ± 37.87||182.44 ± 32.68||0.952|
|LDL cholesterol (mg/dL)||123.94 ± 30.77||118.53 ± 28.25||0.398|
|HDL cholesterol (mg/dL)|| 39.48 ± 9.37|| 45.38 ± 11.41||0.01|
|TG (mg/dL)|| 92.28 ± 52.66|| 93.37 ± 47.17||0.919|
|Medical treatment (number)|
| None|| 6|| || |
| Topical steroid/calcipotriol|| 26|| || |
| Etanercept|| 1|| || |
| Acitretin|| 10|| || |
Ultrasonographic findings of the study subjects
All subjects tolerated the ultrasonographic examination well. None of the psoriasis patients or healthy control subjects refused testing. The ultrasonographic results are presented in Table 2. The mean IMT values of the right, left and averaged CCA of the psoriasis patients were significantly higher, compared with the controls (0.607 ± 0.144 mm vs. 0.532 ± 0.101 mm, 0.611 ± 0.157 mm vs. 0.521 ± 0.117 mm, and 0.609 ± 0.146 mm vs. 0.526 ± 0.104 mm; P = 0.006, P = 0.003 and P = 0.003, respectively). The mean FMD and NTD values of the psoriasis patients were significantly lower, compared with the controls (13.36 ± 6.39 mm vs. 19.60 ± 11.23 mm and 21.08 ± 8.38 mm vs. 26.85 ± 12.38 mm; P = 0.002 and P = 0.013, respectively). In a subgroup analysis of the non-smoking subjects, the averaged carotid IMT, FMD and NTD also differed significantly between the groups (P = 0.005, P = 0.022, and P = 0.046, respectively).
Table 2. Ultrasonographic results of the study subjects
|Right CCA IMT (mm)||0.607 ± 0.144||0.532 ± 0.101||–0.129 to –0.022||0.006|
|Left CCA IMT (mm)||0.611 ± 0.157||0.521 ± 0.117||–0.149 to –0.030||0.003|
|Averaged CCA IMT (mm)||0.609 ± 0.146||0.526 ± 0.104||–0.137 to –0.028||0.003|
|Plaque of right CCA (number)||3||2||–||0.645|
|Plaque of left CCA (number)||1||3||–||0.306|
|Baseline diameter of BA (mm)||3.52 ± 0.65||3.33 ± 0.63||–0.47 to 0.08||0.162|
|FMD (%)||13.4 ± 6.4||19.6 ± 11.2|| 2.3 to 10.2||0.002|
|NTD (%)||21.1 ± 8.4||26.9 ± 12.4|| 1.2 to 10.3||0.013|
In the analysis of covariance, the adjusted HDL levels were used to compare the subclinical atherosclerosis indicators in patients and controls. The differences in the average IMT and FMD measurements were still statistically significant between the two groups (P = 0.006 and P = 0.01, respectively).
Multiple linear regression analyses of factors associated with subclinical atherosclerosis indicators in all study patients and psoriasis patients only
Table 3 shows the results of multiple linear regression analyses of factors associated with the carotid artery IMT, FMD and NTD in the entire group of 86 study subjects. Multiple linear regression analysis of the factors associated with carotid artery IMT in all of the study subjects, in the model that included age, WHR, BMI, total cholesterol, LDL cholesterol and the presence of psoriasis as independent variables, indicated that age and the presence of psoriasis were significantly associated with IMT (Table 3).
Table 3. Multiple linear regression analyses factors associated with carotid artery IMT, FMD and NTD in the entire group of the 86 study subjects
|WHR||–0.097|| 0.098|| 0.052|
|LDL cholesterol|| 0.106||–0.033||–|
|HDL Cholesterol||–|| 0.040|| 0.123|
|Presence of psoriasis|| 0.310***||–0.320**||–0.226*|
|R2 (multiple coefficient of determination)|| 0.647***|| 0.336***|| 0.249**|
Multiple linear regression analysis of the factors associated with FMD in all of the study subjects, in the model that included age, sex, WHR, LDL, HDL cholesterol and the presence of psoriasis as independent variables, indicated that age, sex, and the presence of psoriasis were significantly associated with FMD (Table 3). Multiple linear regression analysis of the factors associated with NTD in all of the study subjects, in the model that included age, sex, WHR, BMI, HDL cholesterol and the presence of psoriasis as independent variables, indicated that age and the presence of psoriasis were significantly associated with NTD (Table 3).
Table 4 shows the results of multiple linear regression analyses of factors associated with carotid artery IMT, FMD and NTD in the 43 psoriasis patients. The model indicates that the duration of psoriasis was significantly associated with FMD, independent of age and WHR (Table 4). However, no association was found between the duration of psoriasis and either IMT or NTD (Table 4).
Table 4. Multiple linear regression analyses factors associated with carotid artery IMT, FMD and NTD in the 43 psoriasis patients
|Total cholesterol|| 0.100||–||–|
|Duration of disease||–0.006||–0.259*||–|
|R2 (multiple coefficient of determination)|| 0.619***|| 0.449***|| 0.163*|
Association of therapies, PASI score and lipid levels with subclinical atherosclerosis indicators
The Pearson correlation test indicated that the PASI score was not associated with subclinical atherosclerosis indicators (P > 0.05). No association was found between the therapies and the subclinical atherosclerosis indicators or lipid levels (P > 0.05). In a subgroup analysis of the psoriasis patients, the subclinical atherosclerosis indicators did not differ significantly between the psoriasis patients who were and were not taking acitretin (P > 0.05).
Several studies have shown that psoriasis is a risk factor for increased cardiovascular diseases. However, these studies have focused on highly selected psoriasis patients, such as those hospitalized for their disease or with multiple comorbidities, including diabetes mellitus, obesity, hypertension and smoking.5,6,15–19 These studies describe findings of manifest atherosclerosis, but give limited information on early, subclinical changes in psoriasis (patients with psoriatic arthritis only) without clinically evident cardiovascular disease. Gonzalez-Juanatey et al. reported impaired endothelial function and increased IMT of the carotid arteries in psoriatic arthritis patients.20,21 Kimhi et al. also found that patients with psoriatic arthritis had greater IMT than healthy controls.22
In this study, we found an increased IMT of the carotid arteries and impaired endothelial function (FMD) in psoriasis patients, compared to healthy controls, reflecting subclinical atherosclerosis. FMD was significantly associated with the duration of disease, suggesting that the long-standing inflammation is responsible for subclinical atherosclerosis. Multiple linear regression analysis also showed that the presence of psoriasis was an independent risk factor associated with IMT, FMD and NTD. However, we failed to detect any significant association between carotid artery IMT and disease duration. In a large series of patients with SLE, Manzi et al. also failed to show an association between disease duration and carotid artery IMT.12 The literature contains some conflicting data regarding carotid artery IMT measurements for evaluating premature atherosclerosis, particularly in relatively young individuals with chronic inflammatory disease.11 Our patients also were relatively young (mean age, 38.5 years), which might have resulted in the failure to find a significant association.
The exact mechanism of the predisposition to cardiovascular disease in psoriasis has not been explained satisfactorily. It has been suggested that three factors contribute to the cardiovascular risk profile in psoriasis patients. First, systemic and chronic inflammation due to the persistent secretion of tumour necrosis factor-α and other pro-inflammatory cytokines plays a major role in the excessively high cardiovascular risk.3,4 Second, comorbidities, such as increased smoking, diabetes mellitus, hypertension, metabolic syndrome and dyslipidaemia in patients with psoriasis, could all contribute to atherosclerosis.4–6,19,23,24 Comparing both groups, we matched the patients for age and sex. There were no significant differences in smoking habit, BMI, WHR, total cholesterol, LDL cholesterol or TG between the psoriasis patients and healthy controls. Only the mean HDL cholesterol was significantly lower in the psoriasis patients, compared with the controls. This concurs with two recent studies.23,25 The mean differences in the IMT and FMD between the groups were also significant in the analysis of covariance adjusted for the HDL. We failed to detect any correlation between the lipid levels and subclinical atherosclerosis indicators. We excluded patients with diabetes mellitus or hypertension from the study.
The third factor is the atherogenic side effects of systemic therapy in psoriasis. None of our patients had been treated with methotrexate, cyclosporine, or systemic steroids, all of which can promote atherosclerosis.26–28 Ten of our patients had received systemic acitretin, while a single patient had been treated with etanercept. Twenty-six of the patients had received topical therapies like corticoids and calcipotriol, and the remaining six patients had not taken any medication. One of the most important side effects of acitretin is dyslipidaemia.29 However, we found no association between acitretin use and lipid levels. The reasons for the dyslipidaemia in psoriasis patients have not been explained satisfactorily in the literature. However, it has been suggested that chronic inflammation promotes dislipidemia.30 In our study, the subclinical atherosclerosis indicators did not differ significantly between psoriasis patients who were and were not taking acitretin. In addition, we failed to detect any significant association between subclinical atherosclerosis indicators and the therapies. There was no correlation between the PASI scores and subclinical atherosclerosis indicators. Kimhi et al. also failed to demonstrate any correlation between the carotid IMT and PASI scores in patients with psoriatic arthritis.22 Psoriasis is a chronic disease characterized by exacerbations and remissions; therefore, the PASI scores often change over time, mainly due to therapy. Consequently, the calculated cumulative PASI scores may be a more reliable predictor of subclinical atherosclerosis. The fact that PASI is not a stable parameter may explain why we failed to detect a significant association between the subclinical atherosclerosis indicators and PASI scores.
In our study, there was a significant difference in NTD between psoriasis patients and controls. Nitroglycerin acts an endothelium-independent, smooth muscle-dependent dilator.31 Some studies have shown that impaired smooth muscle-dependent dilatation (i.e. nitroglycerin-dependent dilatation or NTD) occurs independently of impaired endothelium-dependent dilation in adults at risk of atherosclerosis.32 In our study, the impaired NTD in psoriasis patients compared with healthy controls may be attributed to the risk of subclinical atherosclerosis.
Our study has several limitations. Since there were no patients on systemic therapies like systemic methotrexate or cyclosporine, we could not analyse the associations with systemic therapies and the subclinical atherosclerosis indicators. Moreover, the study population was too small to analyse the therapies. Another limitation is the absence of longitudinal quantification of the cumulative PASI scores of the psoriasis patients.
In conclusion, the psoriasis patients exhibited impaired endothelial function and smooth-muscle-dependent dilatation, and the IMT of the common carotid arteries was thicker than in the healthy controls. Our data showed that the presence of psoriasis was an independent risk factor for subclinical atherosclerosis, possibly due to chronic inflammation. Our data also suggest that the use of systemic retinoids or topical treatments primarily for clinical recovery may not adequately control the chronic atherosclerotic process. Further studies are needed to clarify the relationship between the therapy and atherosclerosis.
Background Psoriasis is associated with an increased risk of atherosclerosis. This study compared subclinical atherosclerosis of the carotid and brachial arteries in psoriasis vulgaris patients and healthy controls using high-resolution ultrasonography.
Methods We studied 43 psoriasis patients and 43 healthy controls matched for age and sex. Flow-mediated dilatation (FMD) and nitroglycerin-induced dilatation (NTD) of the brachial artery and intima-media thickness (IMT) of the common carotid arteries (CCA) were measured ultrasonographically. Diabetes mellitus, hypertension, renal failure, a history of cardiovascular or cerebrovascular disease were exclusion criteria. Subjects who were receiving lipid-lowering therapy, antihypertensive or anti-aggregant drugs, nitrates or long-term systemic steroids were also excluded.
Results The mean IMT values of the right, left and averaged CCA of the psoriasis patients were significantly higher, compared with the controls (0.607 ± 0.144 mm vs. 0.532 ± 0.101 mm, 0.611 ± 0.157 mm vs. 0.521 ± 0.117 mm, and 0.609 ± 0.146 mm vs. 0.526 ± 0.104 mm; P = 0.006, P = 0.003 and P = 0.003, respectively). The mean FMD and NTD values of the psoriasis patients were significantly lower, compared with the controls (13.36 ± 6.39 mm vs. 19.60 ± 11.23 mm and 21.08 ± 8.38 mm vs. 26.85 ± 12.38 mm; P = 0.002 and P = 0.013, respectively). Multiple linear regression analysis revealed a significant association between psoriasis and the IMT, FMD and NTD. Moreover, the FMD in psoriasis patients was associated with disease duration.
Conclusion Psoriasis patients had impaired endothelial function and thicker IMT of the CCA, compared with the healthy control subjects. The presence of psoriasis was an independent risk factor for subclinical atherosclerosis.