Cardiovascular Risk Factors in Patients with Lichen Planus
Salvador Arias-Santiago, PhD, a,b Agustn Buenda-Eisman, PhD, b Jos Aneiros-Fernndez, MD, c Mara Sierra Girn-Prieto, MD, d Mara Teresa Gutirrez-Salmern, PhD, a,b Valentn Garca Mellado, PhD, d Ramn Naranjo-Sintes, PhD a,b a Department of Dermatology, San Cecilio University Hospital, Granada, Spain; b Department of Dermatology and c Department of Histopathology, School of Medicine, Granada University, Spain; d Department of Dermatology, Virgen de las Nieves University Hospital, Granada, Spain. ABSTRACT BACKGROUND: Chronic inammation was found to play an important role in the development of cardio- vascular risk factors. Recently a case-control study found that lichen planus was associated with dyslip- idemia in a large series of patients. However, no data were presented about lipid values, glucose levels, or blood pressure. OBJECTIVE: The objective of this case-control study was to evaluate cardiovascular risk factors included in Adult Treatment Panel III criteria for metabolic syndrome in men and women with lichen planus and in healthy controls. PATIENTS AND METHODS: This case-control study included 200 patients, 100 with lichen planus (50 men and 50 women) and 100 controls consecutively admitted to the outpatient clinic in Dermatology depart- ments in Granada, Spain. RESULTS: Analysis of metabolic syndrome parameters revealed a higher signicant prevalence of dyslip- idemia in patients with lichen planus. No signicant differences were observed in glucose levels, abdom- inal obesity, or blood pressure. Elevated levels of C-reactive protein, erythrocyte sedimentation rate, and brinogen were noted in patients with lichen planus. Adjusted odds ratio for dyslipidemia in patients with lichen planus was 2.85 (95% condence interval, 1.33-5.09; P.001). CONCLUSION: Chronic inammation in patients with lichen planus may explain the association with dyslipidemia. Lipid levels screening in men or women with lichen planus may be useful to detect individuals at risk and start preventive treatment against the development of cardiovascular disease. 2011 Elsevier Inc. All rights reserved. The American Journal of Medicine (2011) 124, 543-548 KEYWORDS: Cardiovascular risk factors; Comorbidity; Dyslipidemia; Lichen planus; Metabolic syndrome Lichen planus is an idiopathic inammatory disease that af- fects the skin and the mucous membranes. Although the etiol- ogy and pathogenesis are not fully understood, it is believed that lichen planus represents a T-cell-mediated inammatory disorder. Inammation produces disturbances of lipid metab- olism such as serum increases of triglycerides or decreases of high-density lipoprotein cholesterol. These lipid disturbances linked to chronic inammation participate in the increase of cardiovascular risk associated with dyslipidemia. Some skin diseases such as androgenetic alopecia 1-4 and psoriasis 5-7 have been associated with cardiovascular risk fac- tors; the proinammatory situation that underlies alopecia and psoriasis may explain this association. Recently, a case-control study found that lichen planus was associated with dyslipide- mia in a large series of patients; 8 however, no data were presented about lipid values, glucose levels, abdominal obe- sity, or blood pressure in patient or controls. Also, authors did not differentiate between lichen planus and lichenoid drug reactions that in some cases are related to several drugs, in- cluding HMG-CoA reductase inhibitors (uvastatin and lova- statin), which are used to treat dyslipidemia, 9,10 or other drugs prescribed for hypertension. 11 In addition, some drugs used to Funding: None. Conict of Interest: None. Authorship: All authors participated sufciently to take public respon- sibility for appropriate portions of the work, had access to the data and a role in writing the manuscript, and approved the submission of the man- uscript. Requests for reprints should be addressed to Salvador Arias-Santiago, PhD, San Cecilio University Hospital, Av Dr. Oloriz 16, Granada 18012, Spain. E-mail address: salvadorarias@hotmail.es 0002-9343/$ -see front matter 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2010.12.025 treat lichen planus, such as retinoic acid, methotrexate, or systemic corticosteroids, can elevate lipid levels. Psoriasis, which is a chronic inammatory skin disease like lichen planus, is associated with an increased risk for cardiovascular risk factors 5-7 including hypertension, diabe- tes, obesity, metabolic syndrome, and dyslipidemia. Several cyto- kines (tumor necrosis factor [TNF -], interleukin [IL]-2, IL-6) have been implicated in the increased lipid levels in these pa- tients. Also, TNF- and interferon- have been shown to be present at high concentrations in cutaneous le- sions of lichen planus. Knowledge of the distribution of cardiovascular risk factors in patients with lichen planus would allow appropriate primary and secondary preventive measures to be applied. The objective of this retrospective case-control study was to analyze the presence of the cardiovascular risk factors in- cluded in the Adult Treatment Plan (ATP)-III metabolic syndrome criteria in males and females with lichen planus and in healthy controls, exclud- ing lichen planus-like eruption and systemic treatment for lichen planus. SUBJECTS AND METHODS Study Subjects This case-control study included 200 patients consecutively admitted to the outpatient clinic (Dermatology departments of San Cecilio and Virgen de las Nieves Hospitals, Granada, Spain), 100 with lichen planus (50 women and 50 men) and 100 controls (50 women and 50 men) with other skin diseases other than lichen planus (mainly nevi, seborrheic keratosis, actinic keratosis, verruca, or basal cell carcinoma). Patients with lichen planus are likely to be representative of patients with lichen planus who present at our hospitals. Diagnosis of lichen planus was based on clinical ndings conrmed with biopsy. Inclusion criteria were: men and women 18 years old, presence of lichen planus affecting the skin or mucosa, and signing of informed consent to study participation. Exclusion criteria were: lichenoid drug eruption and receiving treatment for lichen planus such as systemic corticosteroids, retinoic acid, or methotrexate. Clinical Parameters and Lipids Levels Measurements The weight, height, and abdominal circumference of sub- jects were measured, and their body mass index (BMI, kg/m 2 ) was calculated. Systolic and diastolic blood pressure was measured after a 5-minute rest and again 10 minutes later, recording the mean value. Serum total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose lev- els, brinogen, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels were studied in samples drawn between 8 and 9 AM after a 12-hour fasting period. In addition, cholesterol total/ HDL-C and LDL-C/HDL-C were calculated. These data were col- lected before starting systemic treat- ment for the disease to avoid dys- lipidemia associated with treatment. Data also were gathered on age, sex, smoking, alcohol consumption, sed- entarism, hypothyroidism, and per- sonal or familial history of cardio- vascular disease. Prevalence of metabolic syndrome (MS) was cal- culated according to ATP-III crite- ria; MS was dened by the presence of 3 of the following: 12 (abdominal circumference 102 cm in males and 88 cm in females; hypertri- glyceridemia 150 mg/dL, HDL-C 40 mg/dL in males and 50 mg/dL in females, blood pres- sure 130/85 mm Hg, or glucose levels 110 mg/dL). The presence of dyslipidemia was dened if one of the following parameters were present: triglycerides 150 mg/ dL, total cholesterol 200 mg/dL, LDL-C 130 mg/dL, or the patient received treatment for dyslipidemia. Statistical Analyses The statistical analyses were performed with the SPSS/PC software (Version 15.0 for Windows; SPSS Inc., Chicago, Ill). Two-sample Students t test was used to compare mean values of quantitative variables as the 2 samples were obtained independently, the Shapiro-Wilk test to examine the normality of their distribution, and the Levene test to study the variance. Qualitative variables were analyzed with chi-squared test. Correlations among variables were studied by using the Pearson coefcient and exponential regression technique. Binary logistic regression models (Wald method), obtaining estimates adjusted odds ratios (OR) and their 95% condence intervals were used to mea- sure the association between lichen planus and dyslipidemia in a multivariate analysis. P .05 was considered signi- cant in all analyses. RESULTS A total of 200 patients were studied, 100 with lichen planus and 100 controls. All of the patients had cutaneous involve- ment, 69% (64% of men and 74% of women, P.38) presented lesions in oral mucosa, 10% ungueal affection, and 7% presented lichen planus pilaris. Twelve patients were replaced because they had lichen planus-like reaction CLINICAL SIGNIFICANCE Cardiovascular risk factors have been associated with some inammatory skin diseases such as psoriasis. Patients with lichen planus presented higher lipid levels and acute phase re- actants; chronic inammation may ex- plain these ndings. Cardiovascular risk factors screening in patients with lichen planus may be use- ful to detect individuals at risk and start preventive treatment. 544 The American Journal of Medicine, Vol 124, No 6, June 2011 associated with drugs according to the method proposed by Naranjo et al 13 and Edwards scale. 14 Hepatitis C virus infection was detected in 12% of patients and all of them had oral mucosa affection. Mean age was 47.8 (SD 9.4) years for women with lichen planus and 46.9 (SD 8.7) years for men with lichen planus (P.62). Mean time since lichen planus onset was 1.8 years (SD 0.9) for women and 1.6 years (SD 1.1) for men (P.32). Mean age, weight, height, BMI, tobacco, and sedentarism are summarized in Table 1 for patients with lichen planus and their respective controls. Men and women with lichen planus differed in some of the above parameters, as men with lichen planus showed higher height (172.8 vs 161.8 cm; P .0001) and weight (79.9 vs 67.8 kg; P .0001) than women with lichen planus. No signicant differences between groups were found in tobacco or alcohol consumption, sedentarism, familial dys- lipidemia, hypothyroidism, or personal or familial history of cardiovascular disease. Also, no signicant differences were found in antihypertensives (13% vs 16%; P.6), anticho- lesterolemics (11% vs 7%; P.45), or oral antidiabetics intake (9% vs 6%; P.59) between patients with lichen planus and controls, respectively. ATP-III criteria for MS were met by 27% of the patients with lichen planus versus 20% of the controls (P.31). MS was not signicantly more frequent (P.65) in the lichen planus males (30%) than in lichen planus females (24%). Differences in MS parameters between patients with lichen planus and controls are listed in Table 2. Men with lichen planus presented higher signicant abdominal perimeter (P.0001), systolic and diastolic blood pressure (P .0001), and lower signicant HDL-C values (P.0015) than women with lichen planus. The MS criteria most fre- quently recorded in males and females with lichen planus were hypertriglyceridemia, abdominal obesity, and HDL-C (Table 3). LDL-C, total cholesterol, total cholesterol/HDL-C, and LDL-C/HDL-C are listed in Table 4. Men and women with lichen planus showed higher signicant mean values than controls for all the parameters. Men with lichen planus presented higher signicant total cholesterol/HDL (P.02) and LDL-C/HDL-C (P.01) than women with lichen pla- nus. There were no signicant differences in lipid levels between patients with oral and cutaneous lichen planus and patients with hepatitis C virus infection (P .05). Table 1 Mean (SD) Age, Weight, Height, BMI, Mean Time with Lichen Planus, Tobacco (%), and Sedentarism (%) in Men and Women with Lichen Planus and their Respective Controls Patients (n 200) P Value Men (n 100) P Value Women (n 100) P Value LP No LP LP No LP LP No LP Age (years) 47.4 (9.0) 48.3 (7.0) .40 46.9 (8.7) 47.3 (8.9) .82 47.8 (9.4) 49.3 (4.1) .30 Weight (kg) 73.9 (12.7) 73.6 (15.1) .89 79.9 (11.5) 78.8 (12.7) .63 67.8 (10.9) 68.1 (15.7) .91 Height (cm) 167.4 (9.5) 168.9 (9.6) .30 172.8 (8.9) 174.9 (7.7) .20 161.8 (6.4) 162.5 (6.9) .62 BMI (Kg/m 2 ) 26.4 (4.5) 25.8 (4.9) .32 26.8 (3.9) 25.8 (4.5) .23 26.1 (5.0) 25.7 (5.3) .77 Sedentarism (%) 56% (56) 53% (53) .77 54% (27) 50% (25) .84 58% (29) 56% (28) .9 Tobacco (%) 25% (25) 26% (26) .9 22% (11) 26% (13) .81 28% (14) 26% (13) .9 Mean time with LP (years) 1.7 (1) 1.8 (0.9) 1.6 (1.1) BMI body mass index; LP lichen planus. Table 2 Analysis of the ATP-III Metabolic Syndrome Criteria (Mean, SD) in Men and Women with Lichen Planus and their Respective Controls Patients (n 200) P Value Men (n 100) P Value Women (n 100) P Value LP No LP LP No LP LP No LP Abdominal perimeter (cm) 91.2 (9.0) 89.4 (9.5) .17 97.8 (8.9) 96.5 (9.2) .47 84.6 (9.4) 82.8 (10.1) .35 Triglycerides (mg/dL) 149.5 (86.6) 103.7 (81.2) .0002 159.4 (90.1) 115.3 (88.3) .01 139.5 (83.3) 92.2 (75.3) .003 HDL-C (mg/dL) 54.5 (12.9) 62.2 (14.4) .0001 50.3 (12.2) 56.9 (13.3) .01 58.8 (13.7) 67.5 (15.5) .002 Systolic BP (mm Hg) 117.8 (15.1) 114.6 (15.5) .14 124.5 (15.6) 121.3 (16.3) .31 111.2 (14.9) 107.9 (14.6) .26 Diastolic BP (mm Hg) 76.6 (8.5) 75.3 (8.3) .27 81.4 (9.2) 80.2 (8.8) .50 71.9 (8.1) 70.5 (7.7) .37 Glucose levels (mg/dL) 91.4 (36.1) 84.3 (33.2) .14 92.7 (36.6) 84.5 (35.3) .25 90.1 (35.7) 84.2 (31.2) .39 ATP-III Adult Treatment Plan III; LP lichen planus; HDL-C high-density lipoprotein cholesterol; BP blood pressure. 545 Arias-Santiago et al Risk Factors and Lichen Planus Table 5 shows the mean brinogen, ESR, and CRP values in the study groups. Elevated levels of CRP, ESR, and brinogen were noted in patients with lichen planus. A positive signicant correlation was found between triglyc- eride levels and CRP (r 0.34, P.01). The prevalence of dyslipidemia in patients with lichen planus was 61%, and 33% for controls (P.0001; OR 3.17; 95% condent interval [CI], 1.77-5.66). Sixty-eight percent (OR 3.46; 95% CI, 1.52-7.9; P.002) of men with lichen planus and 54% (OR 3.01; 95% CI, 1.31-6.92; P.014) of women with lichen planus presented dyslipidemia (P .21). A multivariate binary regression model demonstrated that lichen planus was associated with dyslipidemia, even after controlling for confounders including age, sex, BMI, glucose levels, and CRP (OR 2.85; 95% CI, 1.33-5.09; P.001). DISCUSSION Prevalence of MS was similar in patients with lichen planus and controls; however, this study found higher lipid levels and acute phase reactants in patients with lichen planus. Lipid parameters were different in men and women with lichen planus. After controlling for sex, age, BMI, glucose levels, and CRP, patients with lichen planus presented higher risk for dyslipidemia. The association of lichen planus with dyslipidemia has been reported in a case report 15 and in a case-control study; 8 however, no data were specied about lipids levels or treat- ments, and some drugs used for dyslipidemia are associated with lichen planus-like eruption, and many drugs used for the treatment of lichen planus (systemic corticosteroids, retinoic acid, or methotrexate) also are associated with dys- lipidemia. We have avoided this bias, excluding lichenoid drug eruptions, and all the patients enrolled in the study had not received systemic treatment for the disease. Also, lichen planus has been associated with hyperglycemia and diabe- tes, 16,17 but we have not found signicant differences in glucose levels between patients and controls. Inammation plays a very important role in the devel- opment of dyslipidemia. Patients with chronic diseases (eg, systemic lupus erythematous, rheumatoid arthritis) show decreased levels of HDL-C and hypertriglyceridemia, with a positive correlation with cytokine levels. 18 In the present study, we found a positive signicant correlation between triglyceride levels and CRP. Psoriasis, which is another chronic inammatory skin disease, has been recently related to dyslipidemia in the context of MS. 5-7 The more frequent presence of chronic inammation parameters in patients with psoriasis has been cited to explain the relationship with cardiovascular disease. Several cytokines such as TNF-, IL-2, and IL-6 have been implicated in the increased lipids levels in these patients. IL-6 also is linked to dyslipidemia, MS, and atherosclerosis. Otherwise, lichen planus is an immune-mediated disease and antigens are processed by Langerhans cells and then presented to T lymphocytes. This stimulated lymphocytic inltrate is epidermotropic and at- Table 3 Prevalence of Metabolic Syndrome Criteria (%) in Men and Women with Lichen Planus and their Respective Controls Men (n 100) P Value Women (n 100) P Value LP No LP LP No LP Abdominal perimeter 44% 38% .68 46% 40% .68 Triglycerides 62% 30% .002 48% 20% .006 HDL-C 42% 18% .016 44% 20% .018 Systolic BP 32% 28% .82 28% 22% .64 Diastolic BP 34% 28% .66 22% 18% .80 Glucose levels 16% 12% .77 14% 10% .75 LP lichen planus; HDL-C high-density lipoprotein cholesterol; BP blood pressure. Table 4 Mean (SD) LDL-C (mg/dL), Total Cholesterol (mg/dL), Total Cholesterol/HDL and LDL-C/HDL-C in Patients with Lichen Planus and their Respective Controls Patients (n 200) P Value Men (n 100) P Value Women (n 100) P Value LP No LP LP No LP LP No LP LDL-C (mg/dL) 120.1 (30.0) 103.9 (28.9) .0001 124.2 (29.2) 107.6 (33.5) .01 115.7 (30.5) 100 (22.7) .006 Total cholesterol (mg/dL) 200.1 (35.6) 183.4 (35.8) .001 201.3 (32.1) 185.1 (37.8) .023 198.8 (39.4) 181.7 (33.8) .026 Total cholesterol/HDL-C 3.7 (1.2) 2.9 (1.1) .0001 4.0 (1.2) 3.2 (1.2) .0012 3.4 (1.4) 2.6 (0.7) .0006 LDL-C/HDL-C 2.2 (1.0) 1.6 (0.8) .0001 2.4 (0.9) 1.8 (0.9) .0012 1.9 (1.1) 1.4 (0.7) .081 LDL-C low-density lipoprotein cholesterol; HDL-C high-density lipoprotein cholesterol; LP lichen planus. 546 The American Journal of Medicine, Vol 124, No 6, June 2011 tacks keratinocytes, resulting in generation of reactive oxygen species. During this lymphocytotoxic process, the keratinocytes release more cytokines that attract more lymphocytes. These cytokines such as TNF-, IL-6, IL-10, and IL-4, involved in lichen planus pathogenesis, could explain the association with dyslipidemia, as chronic in- ammation has been suggested as a component of the MS. Similar to psoriasis, lichen planus might be a marker for dyslipidemia. Increased LDL-C/HDL-C ratio has already been consid- ered as a sensitive predictor of cardiovascular risk, and recently, total cholesterol/HDL-C ratio has been found an even better predictor metabolic index for cardiovascular risk in large study. 19 In the present study, patients with lichen planus presented higher values of both ratios. Sharrett et al 20 stated that higher values of triglycerides and low levels of HDL-C were associated with the transition from atheroma to atherothrombosis and therefore, control of these 2 car- diovascular risk factors is essential in patients with subclin- ical disease. MS, according to APT-III criteria, is associated with a higher risk of a cardiovascular event (OR 2.59) in the next 10 years, according to some authors. 21 In the present study, patients with lichen planus presented higher preva- lence of MS, but these differences were not statistically signicant. As dyslipidemia is a very important component of MS, prospective studies with longer follow-up periods may show a higher signicant prevalence of MS in these patients. Although case-control studies can show a possible selec- tion bias, the distribution of the potentially confounding factors as age, weight, height, BMI, tobacco use, sedenta- rism, hypothyroidism, and drug intake were homogeneous in the 2 groups. In the present study, binary logistic regres- sion model showed a higher risk for dyslipidemia in patients with lichen planus after controlling for age, sex, BMI, glu- cose levels, and CRP. Also, case-control studies do not allow the directionality of the association to be ascertained, so more prospective studies with larger numbers of patients are required to conrm these ndings and to analyze the pathogenic mechanisms underlying the increase in cardio- vascular risk in patients with lichen planus. In conclusion, the results obtained indicate an association between lichen planus in male or female patients and dys- lipidemia. Chronic inammation and acute phase reactants may explain these ndings. Lipid levels screening in males or females with lichen planus may be useful to detect individuals at risk and start preventive treatment against the development of cardiovascular disease. References 1. Arias-Santiago S, Gutirrez-Salmern MT, Castellote-Caballero L, Naranjo-Sintes R. Elevated aldosterone levels in patients with andro- genetic alopecia. Br J Dermatol. 2009;161:1196-1198. 2. Arias-Santiago S, Gutierrez-Salmern MT, Buenda-Eisman A, Girn- Prieto MS, Naranjo-Sintes R. Hypertension and aldosterone levels in women with early-onset androgenetic alopecia. Br J Dermatol. 2009; 162:786-789. 3. Arias-Santiago S, Gutirrez-Salmern MT, Castellote-Caballero L, Buenda-Eisman A, Naranjo-Sintes R. Androgenetic alopecia and car- diovascular risk factors in men and women: a comparative study. J Am Acad Dermatol. 2010;63:420-429. 4. Arias-Santiago S, Gutirrez-Salmern MT, Buenda-Eisman A, Girn- Prieto MS, Naranjo-Sintes R. Lipid levels in women with androgenetic alopecia. Int J Dermatol. 2010;49:1340-1342. 5. Gisondi P, Tessari G, Conti A, et al. Prevalence of metabolic syndrome in patients with psoriasis: a hospital-based case-control study. Br J Dermatol. 2007;157:68-73. 6. Ruiz-Carrascosa JC, Arias-Santiago S. Psoriasis and metabolic syn- drome. Piel. 2010;25:133-145. 7. Arias-Santiago S, Ruiz-Carrascosa JC, Girn-Prieto MS, Almazn- Fernndez FM, Naranjo-Sintes R. Prevalence of metabolic syn- drome in patients with severe psoriasis. Actual Medica. 2009;778: 12-17. 8. Dreiher J, Shapiro J, Cohen AD. Lichen planus and dyslipidaemia: a case-control study. Br J Dermatol. 2009;161:626-629. 9. Sebk B, Tth M, Anga B, Harangi F, Schneider I. Lichenoid drug eruption with HMG-CoA reductase inhibitors (uvastatin and lova- statin). Acta Derm Venereol. 2004;84:229-230. 10. Stoebner PE, Michot C, Ligeron C, Durand L, Meynadier J, Meunier L. Simvastatin-induced lichen planus pemphigoides. Ann Dermatol Venereol. 2003;130:187-190. 11. Arias-Santiago S, Aneiros-Fernndez J, Aceituno-Madera P, Burkhardt- Prez P, Naranjo-Sintes R. Hypertrophic lichenoid eruption due to furo- semide. Acta Derm Venereol. 2010;90:78-79. 12. Adult Treatment Panel III. Executive summary on the third report of the National Cholesterol Education Program (NECP). 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Table 5 Mean (SD) CRP, Fibrinogen, ESR in Men and Women with Lichen Planus and their Respective Controls Patients (n 200) P Value Men (n 100) P Value Women (n 100) P Value LP No LP LP No LP LP No LP CRP (mg/dL) 0.53 (0.56) 0.31 (0.45) .004 0.59 (0.72) 0.32 (0.57) .03 0.46 (0.32) 0.31 (0.28) .018 Fibrinogen (mg/dL) 357.9 (77.9) 305.1 (89.3) .001 336.6 (72.2) 292.9 (99) .013 380.5 (78.1) 318.1 (76.7) .0001 ESR (mm/h) 14.2 (12.5) 9.9 (7.5) .004 12.7 (11.6) 7.7 (4.1) .005 15.8 (13.3) 12.3 (9.4) .13 CRP C-reactive protein; ESR erythrocyte sedimentation rate; LP lichen planus. 547 Arias-Santiago et al Risk Factors and Lichen Planus 15. Kurgansky D, Burnett JW. Widespread lichen planus in association with Turners syndrome and multiple endocrinopathies. Cutis. 1994; 54:108-110. 16. Lowe NJ, Cudworth AG, Clough SA, Bullen MF. Carbohydrate me- tabolism in lichen planus. Br J Dermatol. 1976;95:9-13. 17. Romero MA, Seoane J, Varela-Centelles P, Diz Dios P, Garca Pola MJ. Prevalence of diabetes mellitus amongst oral lichen planus pa- tients. Clinical and pathological characteristics. Med Oral. 2002;7: 121-129. 18. Esteve E, Ricart W, Fernndez-Real JM. Dyslipidemia and inamma- tion: an evolutionary conserved mechanism. Clin Nutr. 2005;24:16-31. 19. Lemieux I, Lamarche B, Couillard C, et al. Total cholesterol/HDL cholesterol ratio vs LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease risk in men: the Quebec Cardiovascular Study. Arch Intern Med. 2001;161:2685-2692. 20. Sharrett AR, Sorlie PD, Chambless LE, et al. Relative importance of various risk factors for asymptomatic carotid atherosclerosis versus coronary heart disease incidence: the Atherosclerosis Risk in Commu- nities Study. Am J Epidemiol. 1999;149(9):843-852. 21. Assmann G, Schulte H, Seedorf U. Cardiovascular risk assessment in the metabolic syndrome: results from the Prospective Cardiovascular Munster (PROCAM) Study. Int J Obes (Lond). 2008;32(Suppl 2):S11-S16. 548 The American Journal of Medicine, Vol 124, No 6, June 2011