CED
Clinical dermatology • Original article
Clinical and Experimental Dermatology
Patients with psoriasis have an increased amount of epicardial fat tissue A. Balci,1 M. Celik,2 D. D. Balci,3 S. Karazincir,4 Z. Yonden,5 I. Korkmaz,4 E. Celik3 and E. Egilmez4 1 4
Department of Radiology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey; and Departments of 2Internal Medicine, 3Dermatology, Radiology, and 5Biochemistry, Faculty of Medicine, Mustafa Kemal University, Antakya, Turkey
doi:10.1111/ced.12216
Summary
Background. Psoriasis is associated with coronary artery disease, and ischemic heart disease is associated with increased amounts of epicardial fat tissue (EFT). There has as yet been no study published on the accumulation of EFT in patients with psoriasis. Aim. To compare epicardial fat accumulation and coronary artery calcium score (CACS) in patients with psoriasis and controls. Methods. We enrolled 38 patients with psoriasis and 38 controls matched for age and gender. Epicardial fat area (EFA) and CACS were evaluated by multidetector computed tomography. Results. Mean EFA in patients with psoriasis was significantly higher than in controls (13.8 8.4 vs. 9.7 6.4 cm2, respectively, P = 0.02), but mean CACS did not differ significantly between the two groups (55.2 65.4 vs. 27.8 29.3; P > 0.05). Multiple linear regression analyses indicated that EFA was significantly associated with waist circumference and presence of coronary artery calcification in both patients and controls, whereas EFA was significantly associated waist circumference and age in patients only (P < 0.05). Conclusions. Patients with psoriasis had a higher level of EFA compared with controls, and EFA was independently associated with the presence of CAC in all study subjects.
Introduction Psoriasis is a chronic, inflammatory skin disease, affecting about 2% of the population worldwide.1 Many studies have suggested that psoriasis is associated not only with clinically obvious cardiovascular diseases, but also with subclinical atherosclerosis.2–5 This association can be explained by the chronic, systemic inflammation associated with psoriasis, the presence of psoriasisrelated comorbidities (such as obesity, metabolic syndrome, hypertension, dyslipidaemia and diabetes mellitus) and the atherogenic side-effects of systemic therapies for psoriasis.6–9 Gelfand et al.3 suggested that psoriasis is an independent risk for myocardial Correspondence: Dr Ali Balci, Department of Radiology, Faculty of Medicine, Dokuz Eylul University, Izmir, Inciralti, 35440, Turkey E-mail: [email protected] Conflict of interest: none declared. Accepted for publication 27 April 2013
ª 2013 British Association of Dermatologists
infarction (MI), and young patients with severe psoriasis have the greatest relative risk of MI, even after controlling for traditional cardiovascular risk factors. Epicardial fat tissue (EFT) is the term given to perivascular visceral fat that is deposited along the coronary arteries. Atherosclerotic plaque formation occurs predominantly in coronary arteries that are encased by EFT. The role of EFT in the pathogenesis of coronary artery disease (CAD) has been explained by the expression of adipokines such as leptin, tumour necrosis factor (TNF)-a, resistin, omentin and vispatin from EFT into the coronary artery lumen via the vasa vasorum.10–12 Recent studies have suggested that measurement of EFT could be used for stratifying patients according to their risk of cardiovascular disease.13,14 Coronary artery calcium scoring (CACS) is a relatively new method for assessing cardiovascular risk stratification in the asymptomatic population, and refers to the quantification of calcified plaques in the
Clinical and Experimental Dermatology (2014) 39, pp123–128
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Patients with psoriasis have an increased amount of epicardial fat A. Balci et al.
coronary arteries as detected by computed tomography (CT).15 Two previous studies have shown that patients with psoriasis have a significantly increased prevalence and severity of coronary artery calcification compared with people without psoriasis.16,17 CT provides an accurate, reproducible and reliable assessment of epicardial fat accumulation (EFA).13,14,18 Ultrasonography is a noninvasive, alternative method that can be used to assess for EFA, but not CACS; CT is the only technique that can be used to calculate CACS. Using CT, both EFA and CACS can be quantified accurately in a single scan of the heart. In this study, we compared EFA and CACS in patients with psoriasis and healthy controls.
Methods The study was approved by the ethics committee of our institution, and informed consent was obtained from all subjects. Subjects
We prospectively recruited 38 consecutive patients with psoriasis (26 men, 12 women; mean SD age 42.2 15.0 years, range 23–61) attending our dermatology clinic, and 38 control subjects matched for age and gender (26 men, 12 women; mean SD age 39.8 13.5 years, range 22–63). The sample size was estimated based on the results of a pilot study (n = 20) using sample size calculator software (DSS Research, Fort Worth, TX, USA). In the pilot study, EFA was 14.1 8.2 and 9.9 5.9 cm2 in the psoriasis group and controls, respectively. According to the results, 36 subjects for each group were needed for a power of 80%, showing a relevant change in EFA with 95% CI. Inclusion criteria for both the pilot and main study were age > 18 years and a history of systemic or inpatient treatment for psoriasis. Menopausal status was not considered when enrolling subjects in the study, and cumulative drug doses were not calculated. The main exclusion criterion was presence of known cardiovascular, endocrine or metabolic diseases other than diabetes mellitus or obesity. Controls were recruited from the healthy relatives of the patients with psoriasis (10 subjects), and from patients referred for dermatological conditions other than psoriasis (28 patients), including superficial fungal infections (n = 14), skin neoplasm (squamous cell carcinoma or basal cell carcinoma; n = 4), contact dermatitis (n = 3), urticaria (n = 3), vitiligo (n = 2), lichen
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planus (n = 1) and folliculitis (n = 1). None of the controls had received any systemic treatment for their condition. All subjects in both groups were of the same ethnic origin. Anthropometric data, including age, gender, weight, height, body mass index (BMI) and waist/hip ratio (WHR) were collected for all subjects. BMI was calculated as weight divided by height (kg/m2), and WHR as the ratio of the waist and hip circumferences. Clinical characteristics were recorded, including duration and type of disease, medications, blood pressure and smoking habit. Length of smoking was not calculated. Subjects were considered to have hypertension if they were taking antihypertensive agents or if they had systolic blood pressure of > 135 mmHg or diastolic pressure > 85 mmHg. The current disease severity was determined using the Psoriasis Area and Severity Index (PASI). In all subjects, blood samples were obtained from the antecubital brachial vein after an overnight fast of at least 8 h, and used to measure total cholesterol, lowdensity lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglyceride (TG), glucose, creatinine, and uric acid. All laboratory parameters and anthropometric measurements were performed on the same day as the CT examination. Measuring epicardial fat tissue and coronary artery calcium scoring
Non-enhanced CT was performed to measure CACS and EFA, using an MDCT (multidetector CT) scanner (Aquilion 64 scanner; Toshiba, Tokyo, Japan), using the following parameters: 120 kV and 300 mA, 0.4 rotation time, and 3 mm slice thickness. The scanning area was between the upper level of the carina and about 10 mm beyond the left ventricular apex. All images were transferred to a commercial cardiac dedicated workstation (Vitrea 2; Vital Images Inc., Minnetonka, MN, USA) for further analysis. All measurements were performed by a single radiologist who was blinded to the clinical diagnoses. The EFA was defined by tracing its contour on a single image at the level of the left main coronary artery origin using a described procedure,18 and calculated as the area in mm2, then converted to cm2. Calcification in a coronary artery was deemed to be present if there was a high density corresponding to the coronary artery wall of > 130 Hounsfield units (HU) using the method of Agatston et al.,19 and total CACS was calculated by summing the scores for all coronary arteries according to Agatston et al.
ª 2013 British Association of Dermatologists
Patients with psoriasis have an increased amount of epicardial fat A. Balci et al.
Statistical analysis
Continuous data are expressed as the mean SD, and categorical variables as percentages. The normality of the variables was tested using the Kolmogorov–Smirnov test. Group means were compared using Student’s t-test. The Mann–Whitney U-test was used to compare the means for data that were not distributed normally, and categorical variables were compared using the v² test. Correlations between variables were analysed using Pearson correlation analysis. Multiple linear regression analyses were used to assess independent associations between the EFA and other variables. The variables significantly associated with EFA (P < 0.05) in the Pearson correlation analysis were included as independent variables in the multiple linear regression analysis models. A stepwise selection method was used in all of the multiple linear regression analyses. A two-sided P-value of < 0.05 was used to assess the significance of analyses. The statistical analysis was performed using SPSS software (version 16; SPSS, Chicago, IL, USA).
Results Table 1 describes the main demographic, clinical and laboratory findings of the study population. The two groups were comparable in terms of anthropometric, demographic, clinical and laboratory findings. Of the 38 patients, 23 had received one systemic treatment, 10 had received two treatments, 3 had received three treatments and the remaining 2 had received four treatments. Current medications were: topical steroid/ calcipotriol (n = 11), ultraviolet (UV)B (n = 10); biological therapies (n = 9); methotrexate (n = 4); ciclosporin (n = 2); acitretin (n = 1); and psoralen plus UVA (PUVA; n =1). Mean EFA was significantly higher in the patient group than in the control group (13.8 8.4 vs. 9.7 6.4 cm2; P = 0.018). At least one calcified plaque in any coronary artery was present in 10 patients vs. 6 controls (P > 0.05), and mean CACS calculated in these subjects with at least one calcified plaque in any coronary artery (i.e. in CAC-positive subjects only) did not differ significantly between the two groups (55.2 65.4 vs. 27.8 29.3; P > 0.05) (Table 1). Subjects with a zero CACS (CAC-negative) were not included in this last analysis. Table 2 presents the results of multiple linear regression analyses for factors associated with EFA for the entire group of 76 study subjects and for the 38 patients with psoriasis only. Multiple linear regression
ª 2013 British Association of Dermatologists
Table 1 Demographic, clinical and laboratory features of the
subjects. Patients with psoriasis, n = 38 Age, years Male/female, n Disease duration, years PASI BMI, kg/m2 WHR, % Total cholesterol, mg/dL LDL cholesterol, mg/dL HDL cholesterol, mg/dL Triglyceride, mg/dL FBS, mg/dL Uric acid, mg/dL Agatston score§ Smoking, n (%) Diabetes mellitus, n (%) Hypertension, n (%) Presence of calcified plaque, n (%) Family history of CAD, n (%) EFA, cm2
Controls, n = 38
P
39.8 13.5 26/12
0.99* 1
9.8 9.3 28.8 3.9 96.4 8.6 203.1 33.7
27.4 4.2 94.4 6.5 185.2 38.5
0.12* 0.36* 0.06*
136.2 27.7
124.4 42.1
0.20*
37.6 9.9
41.4 8.9
0.11*
150.2 74.4
130.1 62.6
0.25*
98.1 15.0 4.8 1.6 55.2 65.4 21, 55.3% 2, 5.3%
96.9.4 16.3 4.5 1.2 27.8 29.3 14, 36.8% 1, 2.6%
0.76* 0.52* 0.27† 0.17‡ 0.56‡
6, 15.8%
5, 13.2%
0.74‡
10, 26.3%
6, 15.8%
0.26‡
8, 21.1%
6, 15.8%
0.59‡
13.8 8.4
9.7 6.4
0.02*
42.2 15.0 26/12 14.9 9.5
BMI, body mass index; CAD, coronary artery disease; EFA, epicardial fat area; FBS, fasting blood sugar; PASI, Psoriasis Area Severity Index; WHR, waist to hip ratio. Results are mean SD, unless otherwise specified. *Student’s t-test; †Mann–Whitney U-test; ‡v² test; §analysed only for subjects positive for coronary artery calcification. Bold value indicates significant difference between the groups. Table 2 Multiple linear regression analyses factors associated with epicardial fat area (EFA) in the entire group of the 76 study subjects and patients with psoriasis only. Standard regression coefficients (b) for EFA in Independent variables Waist circumference Age Coronary artery calcification R2‡
Patients with psoriasis only
All study subjects
0.61† 0.27* –
0.60† – 0.23*
0.54†
0.50†
*P < 0.0; †P < 0.001; ‡multiple coefficient of determination.
analyses in all of the study subjects indicated that EFA was significantly associated with waist circumference and the presence of CAC, whereas it was significantly
Clinical and Experimental Dermatology (2014) 39, pp123–128
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associated with waist circumference and age in the patients with psoriasis only (Table 2). No clinical features or laboratory findings were associated with EFA. The type of current therapy or previous systemic medication was not associated with EFA, CACS or anthropometric parameters.
Discussion To our knowledge, this study is the first to document that EFA is increased in patients with psoriasis, compared with control subjects with similar anthropometric features. This study also showed that EFA was independently associated with the presence of CAC in all study subjects. We also investigated the prevalence and severity of CAC in patients with psoriasis and in control subjects. However, there was no significant difference in the prevalence of coronary calcification or degree of coronary atherosclerosis estimated using the mean CACS between the groups. Even when more prevalent and severe CAC was found in patients with psoriasis, compared with controls, the differences did not reach statistical significance. Both Ludwig et al.16 and Yiu et al.17 found that patients with psoriasis had a significantly higher prevalence of, and more severe, CAC compared with controls without psoriasis. However, in the Ludwig et al. study, the mean age of the patients was 49 years and disease duration 23 years, whereas in our study, these were 42 and15 years, respectively. Moreover, in our study, the relatively small number of patients and controls with positive CAC (26.3% of the patients with psoriasis) might have precluded finding a significant difference between the groups in terms of prevalence and severity of CAC. Bachar et al.14 noted a strong positive correlation between epicardial adipose tissue thickness and coronary atherosclerosis quantified by CACS in asymptomatic subjects. We also found a significantly independent association of EFA and the presence of coronary artery calcification in all study subjects. CACS is a promising method for cardiovascular risk stratification in asymptomatic subjects. The presence of coronary artery calcification is a reflection of clinical atherosclerotic disease in the coronary arteries. The significant relationship between the presence of CAC and EFA in our study group, which included asymptomatic subjects, suggests a role for increased EFA in the development of atherosclerotic heart disease in psoriasis. There is growing evidence that psoriasis is associated with accelerated atherosclerosis, although the
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exact mechanisms linking psoriasis and atherosclerotic disease are not fully understood. Pathogenically, the backgrounds of psoriasis and atherosclerosis involve similar inflammatory mechanisms. T-cell-mediated immune events and persistent secretion of TNF-a and pro-inflammatory cytokines are seen in both conditions.6,20 It was reported that the association between psoriasis and MI was independent of psoriatic comorbidities such as diabetes mellitus, hypertension, metabolic syndrome, obesity and dyslipidaemia, and higher levels of smoking.3 EFT is a metabolically active endocrine and paracrine organ that is involved in lipid and energy homeostasis, and secretes inflammatory cytokines that are known to modulate key mechanisms of atherogenesis. Secretion of these inflammatory cytokines from EFT into the neighbouring coronary arteries and the systemic circulation are thought to play an important role in the development of atherosclerotic CAD, as are EFT-related atherogenic pathways, including oxidative stress, inflammation, endothelial dysfunction and vascular remodelling.10–12 Psoriasis is associated with obesity,7 which is an independent risk factor for the development and progression of CAD. There is an association between excess EFT and the degree of obesity.13 We found that patients with psoriasis had more EFT than the controls, even when the anthropometric parameters were comparable between the groups. The origin of EFT has embryological similarities with the development of intra-abdominal fat, which is also a metabolically active visceral adipose tissue.12 Previously, we reported that intra-abdominal visceral fat tissue is increased and associated with metabolic syndrome in patients with psoriasis.21 Waist circumference, a simple anthropometric measurement, is a useful indicator of the amount of intra-abdominal visceral adipose tissue accumulation.22 EFT is strongly correlated with waist circumference and with imaging measurements of intra-abdominal visceral adipose tissue.23 In our study, EFAwas independently associated with waist circumference in both study groups, in accordance with previous studies, but EFA was independently associated with age only in the patient group. The relationship between the amount of EFT and age is controversial; however, it appears to be significant up to 20–40 years of age, but not thereafter.24 The lipid profile might influence EFA and CACS; however, we did not find any significant association between lipid profiles or other laboratory results and EFA or CACS. Clinical findings such as PASI, hypertension and smoking habit were also not associated with EFA or CACS. Systemic therapies used in
ª 2013 British Association of Dermatologists
Patients with psoriasis have an increased amount of epicardial fat A. Balci et al.
patients with psoriasis might affect the metabolic state and the amount of EFT; however, no significant association was found between the number of systemic treatments or type of medication and either EFA or CACS. There are some limitations to our study. First, no noncalcified atherosclerotic plaques or possible arterial stenosis could be detected using the nonenhanced MDCT imaging protocol used to determine CAC. Psoriasis is a genetic disease, and some controls were healthy relatives of patients, thus this could also have affected the MDCT results. Even if the sample size was sufficient to compare EFA between the groups, a larger study population is needed to evaluate CACS and confirm our results
Conclusion In this study, we found for the first time that EFA is increased in patients with psoriasis and that EFA was independently associated with the presence of CAC in all study subjects. Secretion of pro-inflammatory cytokines from the increased amount of EFA affects the coronary arteries locally, and this might be an explanation for the mechanism linking psoriasis and increased risk of CAD.
Learning points ● Psoriasis is associated with CAD. ● A relationship between CAD and increased EFT
has been reported. ● In the current study, patients with psoriasis
had higher levels of EFT compared with controls. ● EFT as independently associated with the pres-
ence of coronarty artery calcification in all study subjects.
References 1 van de Kerkhof PCM, Schalkwijk J. Psoriasis. In: Dermatology, 2nd edn (Bolognia JL, Jorizzo JL, Rapini RP, eds). Philadelphia: Mosby Elsevier, 2008: 115–35. 2 Shapiro J, Cohen AD, David M et al. The association between psoriasis, diabetes mellitus, and atherosclerosis in Israel: a case-control study. J Am Acad Dermatol 2007; 56: 629–34. 3 Gelfand JM, Neimann AL, Shin DB et al. Risk of myocardial infarction in patients with psoriasis. JAMA 2006; 296: 1735–41.
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4 Armstrong AW, Harskamp CT, Ledo L et al. Coronary artery disease in patients with psoriasis referred for coronary angiography. Am J Cardiol 2012; 109: 976–80. 5 Balci DD, Balci A, Karazincir S et al. Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis. J Eur Acad Dermatol Venereol 2009; 23: 1–6. 6 Hansson GK, Robertson AK, S€ oderberg-Naucler C. Inflammation and atherosclerosis. Annu Rev Pathol 2006; 1: 297–329. 7 Neimann AL, Shin DB, Wang X et al. Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol 2006; 55: 829–35. 8 Maxwell SR, Moots RJ, Kendall MJ. Corticosteroids. Do they damage the cardiovascular system? Postgrad Med J 1994; 70: 863–70. 9 Landewe RB, van den Borne BE, Breedveld FC, Dijkmans BA. Methotrexate effects in patients with rheumatoid arthritis with cardiovascular comorbidity. Lancet 2000; 355: 1616–17. 10 Iacobellis G, Malavazos AE, Corsi MM. Epicardial fat: from the biomolecular aspects to the clinical practice. Int J Biochem Cell Biol 2011; 43: 1651–4. 11 Payne GA, Kohr MC, Tune JD. Epicardial perivascular adipose tissue as a therapeutic target in obesity-related coronary artery disease. Br J Pharmacol 2012; 165: 659–69. 12 Sacks HS, Fain JN. Human epicardial adipose tissue: a review. Am Heart J 2007; 153: 907–17. 13 Sarin S, Wenger C, Marwaha A et al. Clinical significance of epicardial fat measured using cardiac multislice computed tomography. Am J Cardiol 2008; 102: 767–71. 14 Bachar GN, Dicker D, Kornowski R, Atar E. Epicardial adipose tissue as a predictor of coronary artery disease in asymptomatic subjects. Am J Cardiol 2012; 110: 534–8. 15 Vliegenthart R, Morris PB. Computed tomography coronary artery calcium scoring: review of evidence base and cost-effectiveness in cardiovascular risk prediction. J Thorac Imaging 2012; 27: 296–303. 16 Ludwig RJ, Herzog C, Rostock A et al. Psoriasis: a possible risk factor for development of coronary artery calcification. Br J Dermatol 2007; 156: 271–6. 17 Yiu KH, Yeung CK, Zhao CT et al. Prevalence and extent of subclinical atherosclerosis in patients with psoriasis. J Intern Med 2012; 273: 27–82. 18 Oyama N, Goto D, Ito YM et al. Single-slice epicardial fat area measurement: do we need to measure the total epicardial fat volume? Jpn J Radiol 2011; 29: 104–9. 19 Agatston AS, Janowitz WR, Hildner FJ et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15: 827–32. 20 Flammer AJ, Ruschitzka F. Psoriasis and atherosclerosis: two plaques, one syndrome? Eur Heart J 2012; 33: 1989–91.
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21 Balci A, Balci DD, Yonden Z et al. Increased amount of visceral fat in patients with psoriasis contributes to metabolic syndrome. Dermatology 2010; 220: 32–7. 22 Li X, Katashima M, Yasumasu T, Li KJ. Visceral fat area, waist circumference and metabolic risk factors in abdominally obese Chinese adults. Biomed Environ Sci 2012; 25: 141–8.
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23 Iacobellis G, Assael F, Ribaudo MC et al. Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction. Obes Res 2003; 11: 304–10. 24 Rabkin SW. Epicardial fat. Properties, function and relationship to obesity. Obes Rev 2007; 8: 253–61.
ª 2013 British Association of Dermatologists
Clinical dermatology • Original article
Clinical and Experimental Dermatology
Patients with psoriasis have an increased amount of epicardial fat tissue A. Balci,1 M. Celik,2 D. D. Balci,3 S. Karazincir,4 Z. Yonden,5 I. Korkmaz,4 E. Celik3 and E. Egilmez4 1 4
Department of Radiology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey; and Departments of 2Internal Medicine, 3Dermatology, Radiology, and 5Biochemistry, Faculty of Medicine, Mustafa Kemal University, Antakya, Turkey
doi:10.1111/ced.12216
Summary
Background. Psoriasis is associated with coronary artery disease, and ischemic heart disease is associated with increased amounts of epicardial fat tissue (EFT). There has as yet been no study published on the accumulation of EFT in patients with psoriasis. Aim. To compare epicardial fat accumulation and coronary artery calcium score (CACS) in patients with psoriasis and controls. Methods. We enrolled 38 patients with psoriasis and 38 controls matched for age and gender. Epicardial fat area (EFA) and CACS were evaluated by multidetector computed tomography. Results. Mean EFA in patients with psoriasis was significantly higher than in controls (13.8 8.4 vs. 9.7 6.4 cm2, respectively, P = 0.02), but mean CACS did not differ significantly between the two groups (55.2 65.4 vs. 27.8 29.3; P > 0.05). Multiple linear regression analyses indicated that EFA was significantly associated with waist circumference and presence of coronary artery calcification in both patients and controls, whereas EFA was significantly associated waist circumference and age in patients only (P < 0.05). Conclusions. Patients with psoriasis had a higher level of EFA compared with controls, and EFA was independently associated with the presence of CAC in all study subjects.
Introduction Psoriasis is a chronic, inflammatory skin disease, affecting about 2% of the population worldwide.1 Many studies have suggested that psoriasis is associated not only with clinically obvious cardiovascular diseases, but also with subclinical atherosclerosis.2–5 This association can be explained by the chronic, systemic inflammation associated with psoriasis, the presence of psoriasisrelated comorbidities (such as obesity, metabolic syndrome, hypertension, dyslipidaemia and diabetes mellitus) and the atherogenic side-effects of systemic therapies for psoriasis.6–9 Gelfand et al.3 suggested that psoriasis is an independent risk for myocardial Correspondence: Dr Ali Balci, Department of Radiology, Faculty of Medicine, Dokuz Eylul University, Izmir, Inciralti, 35440, Turkey E-mail: [email protected] Conflict of interest: none declared. Accepted for publication 27 April 2013
ª 2013 British Association of Dermatologists
infarction (MI), and young patients with severe psoriasis have the greatest relative risk of MI, even after controlling for traditional cardiovascular risk factors. Epicardial fat tissue (EFT) is the term given to perivascular visceral fat that is deposited along the coronary arteries. Atherosclerotic plaque formation occurs predominantly in coronary arteries that are encased by EFT. The role of EFT in the pathogenesis of coronary artery disease (CAD) has been explained by the expression of adipokines such as leptin, tumour necrosis factor (TNF)-a, resistin, omentin and vispatin from EFT into the coronary artery lumen via the vasa vasorum.10–12 Recent studies have suggested that measurement of EFT could be used for stratifying patients according to their risk of cardiovascular disease.13,14 Coronary artery calcium scoring (CACS) is a relatively new method for assessing cardiovascular risk stratification in the asymptomatic population, and refers to the quantification of calcified plaques in the
Clinical and Experimental Dermatology (2014) 39, pp123–128
123
Patients with psoriasis have an increased amount of epicardial fat A. Balci et al.
coronary arteries as detected by computed tomography (CT).15 Two previous studies have shown that patients with psoriasis have a significantly increased prevalence and severity of coronary artery calcification compared with people without psoriasis.16,17 CT provides an accurate, reproducible and reliable assessment of epicardial fat accumulation (EFA).13,14,18 Ultrasonography is a noninvasive, alternative method that can be used to assess for EFA, but not CACS; CT is the only technique that can be used to calculate CACS. Using CT, both EFA and CACS can be quantified accurately in a single scan of the heart. In this study, we compared EFA and CACS in patients with psoriasis and healthy controls.
Methods The study was approved by the ethics committee of our institution, and informed consent was obtained from all subjects. Subjects
We prospectively recruited 38 consecutive patients with psoriasis (26 men, 12 women; mean SD age 42.2 15.0 years, range 23–61) attending our dermatology clinic, and 38 control subjects matched for age and gender (26 men, 12 women; mean SD age 39.8 13.5 years, range 22–63). The sample size was estimated based on the results of a pilot study (n = 20) using sample size calculator software (DSS Research, Fort Worth, TX, USA). In the pilot study, EFA was 14.1 8.2 and 9.9 5.9 cm2 in the psoriasis group and controls, respectively. According to the results, 36 subjects for each group were needed for a power of 80%, showing a relevant change in EFA with 95% CI. Inclusion criteria for both the pilot and main study were age > 18 years and a history of systemic or inpatient treatment for psoriasis. Menopausal status was not considered when enrolling subjects in the study, and cumulative drug doses were not calculated. The main exclusion criterion was presence of known cardiovascular, endocrine or metabolic diseases other than diabetes mellitus or obesity. Controls were recruited from the healthy relatives of the patients with psoriasis (10 subjects), and from patients referred for dermatological conditions other than psoriasis (28 patients), including superficial fungal infections (n = 14), skin neoplasm (squamous cell carcinoma or basal cell carcinoma; n = 4), contact dermatitis (n = 3), urticaria (n = 3), vitiligo (n = 2), lichen
124
Clinical and Experimental Dermatology (2014) 39, pp123–128
planus (n = 1) and folliculitis (n = 1). None of the controls had received any systemic treatment for their condition. All subjects in both groups were of the same ethnic origin. Anthropometric data, including age, gender, weight, height, body mass index (BMI) and waist/hip ratio (WHR) were collected for all subjects. BMI was calculated as weight divided by height (kg/m2), and WHR as the ratio of the waist and hip circumferences. Clinical characteristics were recorded, including duration and type of disease, medications, blood pressure and smoking habit. Length of smoking was not calculated. Subjects were considered to have hypertension if they were taking antihypertensive agents or if they had systolic blood pressure of > 135 mmHg or diastolic pressure > 85 mmHg. The current disease severity was determined using the Psoriasis Area and Severity Index (PASI). In all subjects, blood samples were obtained from the antecubital brachial vein after an overnight fast of at least 8 h, and used to measure total cholesterol, lowdensity lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglyceride (TG), glucose, creatinine, and uric acid. All laboratory parameters and anthropometric measurements were performed on the same day as the CT examination. Measuring epicardial fat tissue and coronary artery calcium scoring
Non-enhanced CT was performed to measure CACS and EFA, using an MDCT (multidetector CT) scanner (Aquilion 64 scanner; Toshiba, Tokyo, Japan), using the following parameters: 120 kV and 300 mA, 0.4 rotation time, and 3 mm slice thickness. The scanning area was between the upper level of the carina and about 10 mm beyond the left ventricular apex. All images were transferred to a commercial cardiac dedicated workstation (Vitrea 2; Vital Images Inc., Minnetonka, MN, USA) for further analysis. All measurements were performed by a single radiologist who was blinded to the clinical diagnoses. The EFA was defined by tracing its contour on a single image at the level of the left main coronary artery origin using a described procedure,18 and calculated as the area in mm2, then converted to cm2. Calcification in a coronary artery was deemed to be present if there was a high density corresponding to the coronary artery wall of > 130 Hounsfield units (HU) using the method of Agatston et al.,19 and total CACS was calculated by summing the scores for all coronary arteries according to Agatston et al.
ª 2013 British Association of Dermatologists
Patients with psoriasis have an increased amount of epicardial fat A. Balci et al.
Statistical analysis
Continuous data are expressed as the mean SD, and categorical variables as percentages. The normality of the variables was tested using the Kolmogorov–Smirnov test. Group means were compared using Student’s t-test. The Mann–Whitney U-test was used to compare the means for data that were not distributed normally, and categorical variables were compared using the v² test. Correlations between variables were analysed using Pearson correlation analysis. Multiple linear regression analyses were used to assess independent associations between the EFA and other variables. The variables significantly associated with EFA (P < 0.05) in the Pearson correlation analysis were included as independent variables in the multiple linear regression analysis models. A stepwise selection method was used in all of the multiple linear regression analyses. A two-sided P-value of < 0.05 was used to assess the significance of analyses. The statistical analysis was performed using SPSS software (version 16; SPSS, Chicago, IL, USA).
Results Table 1 describes the main demographic, clinical and laboratory findings of the study population. The two groups were comparable in terms of anthropometric, demographic, clinical and laboratory findings. Of the 38 patients, 23 had received one systemic treatment, 10 had received two treatments, 3 had received three treatments and the remaining 2 had received four treatments. Current medications were: topical steroid/ calcipotriol (n = 11), ultraviolet (UV)B (n = 10); biological therapies (n = 9); methotrexate (n = 4); ciclosporin (n = 2); acitretin (n = 1); and psoralen plus UVA (PUVA; n =1). Mean EFA was significantly higher in the patient group than in the control group (13.8 8.4 vs. 9.7 6.4 cm2; P = 0.018). At least one calcified plaque in any coronary artery was present in 10 patients vs. 6 controls (P > 0.05), and mean CACS calculated in these subjects with at least one calcified plaque in any coronary artery (i.e. in CAC-positive subjects only) did not differ significantly between the two groups (55.2 65.4 vs. 27.8 29.3; P > 0.05) (Table 1). Subjects with a zero CACS (CAC-negative) were not included in this last analysis. Table 2 presents the results of multiple linear regression analyses for factors associated with EFA for the entire group of 76 study subjects and for the 38 patients with psoriasis only. Multiple linear regression
ª 2013 British Association of Dermatologists
Table 1 Demographic, clinical and laboratory features of the
subjects. Patients with psoriasis, n = 38 Age, years Male/female, n Disease duration, years PASI BMI, kg/m2 WHR, % Total cholesterol, mg/dL LDL cholesterol, mg/dL HDL cholesterol, mg/dL Triglyceride, mg/dL FBS, mg/dL Uric acid, mg/dL Agatston score§ Smoking, n (%) Diabetes mellitus, n (%) Hypertension, n (%) Presence of calcified plaque, n (%) Family history of CAD, n (%) EFA, cm2
Controls, n = 38
P
39.8 13.5 26/12
0.99* 1
9.8 9.3 28.8 3.9 96.4 8.6 203.1 33.7
27.4 4.2 94.4 6.5 185.2 38.5
0.12* 0.36* 0.06*
136.2 27.7
124.4 42.1
0.20*
37.6 9.9
41.4 8.9
0.11*
150.2 74.4
130.1 62.6
0.25*
98.1 15.0 4.8 1.6 55.2 65.4 21, 55.3% 2, 5.3%
96.9.4 16.3 4.5 1.2 27.8 29.3 14, 36.8% 1, 2.6%
0.76* 0.52* 0.27† 0.17‡ 0.56‡
6, 15.8%
5, 13.2%
0.74‡
10, 26.3%
6, 15.8%
0.26‡
8, 21.1%
6, 15.8%
0.59‡
13.8 8.4
9.7 6.4
0.02*
42.2 15.0 26/12 14.9 9.5
BMI, body mass index; CAD, coronary artery disease; EFA, epicardial fat area; FBS, fasting blood sugar; PASI, Psoriasis Area Severity Index; WHR, waist to hip ratio. Results are mean SD, unless otherwise specified. *Student’s t-test; †Mann–Whitney U-test; ‡v² test; §analysed only for subjects positive for coronary artery calcification. Bold value indicates significant difference between the groups. Table 2 Multiple linear regression analyses factors associated with epicardial fat area (EFA) in the entire group of the 76 study subjects and patients with psoriasis only. Standard regression coefficients (b) for EFA in Independent variables Waist circumference Age Coronary artery calcification R2‡
Patients with psoriasis only
All study subjects
0.61† 0.27* –
0.60† – 0.23*
0.54†
0.50†
*P < 0.0; †P < 0.001; ‡multiple coefficient of determination.
analyses in all of the study subjects indicated that EFA was significantly associated with waist circumference and the presence of CAC, whereas it was significantly
Clinical and Experimental Dermatology (2014) 39, pp123–128
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Patients with psoriasis have an increased amount of epicardial fat A. Balci et al.
associated with waist circumference and age in the patients with psoriasis only (Table 2). No clinical features or laboratory findings were associated with EFA. The type of current therapy or previous systemic medication was not associated with EFA, CACS or anthropometric parameters.
Discussion To our knowledge, this study is the first to document that EFA is increased in patients with psoriasis, compared with control subjects with similar anthropometric features. This study also showed that EFA was independently associated with the presence of CAC in all study subjects. We also investigated the prevalence and severity of CAC in patients with psoriasis and in control subjects. However, there was no significant difference in the prevalence of coronary calcification or degree of coronary atherosclerosis estimated using the mean CACS between the groups. Even when more prevalent and severe CAC was found in patients with psoriasis, compared with controls, the differences did not reach statistical significance. Both Ludwig et al.16 and Yiu et al.17 found that patients with psoriasis had a significantly higher prevalence of, and more severe, CAC compared with controls without psoriasis. However, in the Ludwig et al. study, the mean age of the patients was 49 years and disease duration 23 years, whereas in our study, these were 42 and15 years, respectively. Moreover, in our study, the relatively small number of patients and controls with positive CAC (26.3% of the patients with psoriasis) might have precluded finding a significant difference between the groups in terms of prevalence and severity of CAC. Bachar et al.14 noted a strong positive correlation between epicardial adipose tissue thickness and coronary atherosclerosis quantified by CACS in asymptomatic subjects. We also found a significantly independent association of EFA and the presence of coronary artery calcification in all study subjects. CACS is a promising method for cardiovascular risk stratification in asymptomatic subjects. The presence of coronary artery calcification is a reflection of clinical atherosclerotic disease in the coronary arteries. The significant relationship between the presence of CAC and EFA in our study group, which included asymptomatic subjects, suggests a role for increased EFA in the development of atherosclerotic heart disease in psoriasis. There is growing evidence that psoriasis is associated with accelerated atherosclerosis, although the
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exact mechanisms linking psoriasis and atherosclerotic disease are not fully understood. Pathogenically, the backgrounds of psoriasis and atherosclerosis involve similar inflammatory mechanisms. T-cell-mediated immune events and persistent secretion of TNF-a and pro-inflammatory cytokines are seen in both conditions.6,20 It was reported that the association between psoriasis and MI was independent of psoriatic comorbidities such as diabetes mellitus, hypertension, metabolic syndrome, obesity and dyslipidaemia, and higher levels of smoking.3 EFT is a metabolically active endocrine and paracrine organ that is involved in lipid and energy homeostasis, and secretes inflammatory cytokines that are known to modulate key mechanisms of atherogenesis. Secretion of these inflammatory cytokines from EFT into the neighbouring coronary arteries and the systemic circulation are thought to play an important role in the development of atherosclerotic CAD, as are EFT-related atherogenic pathways, including oxidative stress, inflammation, endothelial dysfunction and vascular remodelling.10–12 Psoriasis is associated with obesity,7 which is an independent risk factor for the development and progression of CAD. There is an association between excess EFT and the degree of obesity.13 We found that patients with psoriasis had more EFT than the controls, even when the anthropometric parameters were comparable between the groups. The origin of EFT has embryological similarities with the development of intra-abdominal fat, which is also a metabolically active visceral adipose tissue.12 Previously, we reported that intra-abdominal visceral fat tissue is increased and associated with metabolic syndrome in patients with psoriasis.21 Waist circumference, a simple anthropometric measurement, is a useful indicator of the amount of intra-abdominal visceral adipose tissue accumulation.22 EFT is strongly correlated with waist circumference and with imaging measurements of intra-abdominal visceral adipose tissue.23 In our study, EFAwas independently associated with waist circumference in both study groups, in accordance with previous studies, but EFA was independently associated with age only in the patient group. The relationship between the amount of EFT and age is controversial; however, it appears to be significant up to 20–40 years of age, but not thereafter.24 The lipid profile might influence EFA and CACS; however, we did not find any significant association between lipid profiles or other laboratory results and EFA or CACS. Clinical findings such as PASI, hypertension and smoking habit were also not associated with EFA or CACS. Systemic therapies used in
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Patients with psoriasis have an increased amount of epicardial fat A. Balci et al.
patients with psoriasis might affect the metabolic state and the amount of EFT; however, no significant association was found between the number of systemic treatments or type of medication and either EFA or CACS. There are some limitations to our study. First, no noncalcified atherosclerotic plaques or possible arterial stenosis could be detected using the nonenhanced MDCT imaging protocol used to determine CAC. Psoriasis is a genetic disease, and some controls were healthy relatives of patients, thus this could also have affected the MDCT results. Even if the sample size was sufficient to compare EFA between the groups, a larger study population is needed to evaluate CACS and confirm our results
Conclusion In this study, we found for the first time that EFA is increased in patients with psoriasis and that EFA was independently associated with the presence of CAC in all study subjects. Secretion of pro-inflammatory cytokines from the increased amount of EFA affects the coronary arteries locally, and this might be an explanation for the mechanism linking psoriasis and increased risk of CAD.
Learning points ● Psoriasis is associated with CAD. ● A relationship between CAD and increased EFT
has been reported. ● In the current study, patients with psoriasis
had higher levels of EFT compared with controls. ● EFT as independently associated with the pres-
ence of coronarty artery calcification in all study subjects.
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