CORRESPONDENCE: RESEARCH CORRESPONDENCE
Are Familial Mediterranean Fever (FMF) Patients at Increased Risk for Atherosclerosis? Impaired Endothelial Function and Increased Intima Media Thickness Are Found in FMF
Ali Akdogan, MD,
Meral Calguneri, MD,
Bunyamin Yavuz, MD*,
E. Bengi Arslan, MD,
Umut Kalyoncu, MD,
Levent Sahiner, MD,
Omer Karadag, MD,
Ihsan Ertenli, MD,
Sedat Kiraz, MD,
Kudret Aytemir, MD, FESC,
Deniz Akata, MD,
Lale Tokgozoglu, MD, FESC, FACC and
Ali Oto, MD, FESC, FACC
* Department of Cardiology, Hacettepe University Faculty of Medicine, Hacettepe Hastanesi Kardiyoloji AD, Ankara, 06100, Turkey (Email: bunyamin{at}hacettepe.edu.tr).
To the Editor: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by periodic attacks of fever and serositis caused by mutations in FMF gene (MEFV). Although FMF patients are symptom free between the attacks, subclinical inflammation continues during the attack-free period (1). Patients with inflammatory diseases, such as those with systemic lupus erythematosus and rheumatoid arthritis, are now considered to have an increased risk of atherosclerotic cardiovascular complications. Intima media thickness (IMT) of carotid arteries and endothelial dysfunction are used to define the preclinical atherosclerosis (2). We attempted to determine whether FMF patients have an increased risk of atherosclerosis by assessing endothelium-dependent flow-mediated dilation (FMD) of brachial artery and IMT of carotid arteries. We also investigated the association between these parameters and inflammatory markers.
We studied 43 FMF patients and 29 healthy control subjects. All FMF patients enrolled in the study fulfilled the clinical criteria for FMF (3). Patients with diabetes mellitus, hypertension, atherosclerotic vascular disease, malignancy, amyloidosis, active infectious disease, pregnancy, or other inflammatory diseases were excluded. All subjects had a complete history and physical examination. Clinical and laboratory assessment of FMF patients were performed during an attack-free period. The FMF patients unresponsive to colchicine therapy have been previously defined (4).
Erythrocyte sedimentation rate (ESR) and fibrinogen were measured. Serum glucose and serum lipids were determined by using an autoanalyzer. Serum amyloid A (SAA) was determined by a commercial micro–enzyme-linked immunosorbent assay method, and high-sensitivity C-reactive protein (hs-CRP) was determined by immunonephelometry. Genetic analysis data of FMF patients were obtained from hospital file records.
Endothelial function was assessed by FMD from the brachial artery, and IMT of carotid arteries was measured as previously described (5,6). The maximum IMT (the highest value of the 6 measurements) was used in statistical analysis. The IMT was considered normal when the intima-media complex was  0.9 mm according to the current sonographic criteria. Maximum IMT values of 0.9 to 1.3 mm were considered indicative of thickened intima, and the values >1.3 mm indicated an atherosclerotic plaque (6).
The SPSS version 11.0 software (SPSS Inc., Chicago, Illinois) was used for data analysis. Categorical and numeric variables were tested by chi-square or Fisher exact tests and Student t test or Mann-Whitney U test, respectively. Correlation was tested with Spearman or Pearson correlation coefficients. Analysis of covariance was used to adjust for high-density lipoprotein (HDL) or total cholesterol levels, while checking for the effect of FMF on FMD or maximum IMT. A significance level was set at p < 0.05.
General characteristics of the patients with FMF and control subjects were similar. All FMF patients were on colchicine treatment. Five patients (12%) were considered colchicine nonresponders. None of the patients had proteinuria. Data of genetic analysis were available in 28 patients. The most frequent 3 mutations were M694V (53.6%), V726A (14.9%), and M680I (14.9%). Among 28 patients, 9 patients (32%) had homozygote mutations, 13 patients (46%) had compound heterozygote mutations, 2 patients (7%) had heterozygote mutations, and 1 patient (4%) had complex allele with M694V/M694V-E148Q.
Total cholesterol (164 ± 34 mg/dl vs. 188 ± 46 mg/dl, p = 0.02) and HDL cholesterol (49 ± 14 mg/dl vs. 57 ± 14 mg/dl, p = 0.03) were significantly lower, ESR (median: 7 mm/h [range: 2 to 66 mm/h] vs. median: 5 mm/h [range: 1 to 4 mm/h], p = 0.003), fibrinogen (324.64 ± 77.93 mg/dl vs. 283.80 ± 57.10 mg/dl, p = 0.02), and hs-CRP (3 mg/l [0.2 to 30.4 mg/l] vs. 0.7 mg/l [0.2 to 3.6 mg/l], p = 0.001) were significantly higher in the FMF group. Serum amyloid A (21.82 U/l [4.25 to 300 U/l] vs. 10.33 U/l [6.00 to 89.10 U/l], p = 0.004), FMD (5.7 ± 2.4% vs. 10.8 ± 1.9%, p = 0.001), maximum IMT (0.79 ± 0.18 mm vs. 0.61 ± 0.11 mm, p = 0.001), mean IMT (0.62 ± 0.08 mm vs. 0.53 ± 0.07 mm, p = 0.001) of right carotid arteries, and mean IMT (0.61 ± 0.07 mm vs. 0.53 ± 0.07 mm, p = 0.001) of the left carotid arteries were also significantly higher in the FMF group. The FMD impairment was more prominent in M694V homozygote patients compared with those without this mutation (4.3 ± 1.5% vs. 6.5 ± 2.2%, p = 0.005) (Fig. 1). There was a positive correlation between the maximum IMT of carotid arteries and age (r = 0.29; p = 0.014). Atherosclerotic plaques were detected in 2 of the FMF patients and none of the control group. Using covariance analysis, after adjustment by HDL or total cholesterol separately, the presence of FMF was shown to be a significant risk factor for both increased IMT and decreased FMD (p < 0.001 for all).
Neither FMD nor maximum IMT of carotid arteries were different between colchicine responder and nonresponder patient groups (p = NS for all). Both FMD of brachial artery and IMT of carotid arteries did not correlate with disease duration, age of symptom onset, duration of colchicine treatment, or current colchicine dosage in FMF patients (p = NS for all).
In this study we found that endothelium-dependent FMD was reduced and IMT of the carotid arteries was increased in FMF patients compared with healthy controls. Acute-phase reactant levels were higher in FMF patients as expected. We suggest that ongoing low-grade inflammation may be the cause of the thickened IMT of the carotid arteries and endothelial dysfunction reflected by reduced FMD in FMF patients.
Langevitz et al. (7) found that ischemic heart disease prevalence was 15.5% in FMF patients, which is lower than expected, but our results suggest that there may still be an increased risk for atherosclerotic vascular complications in FMF patients, as in other inflammatory diseases.
Serum lipid changes in FMF patients resemble those in chronic inflammatory diseases, so we think that these changes may be another feature of the ongoing inflammation (8). Other than the effect of FMF disease itself, a decreased HDL cholesterol level was not found to introduce additional risk for the reduced FMD or thickened maximum IMT of carotid arteries in this study. Although the IMTs of carotid arteries were higher in FMF patients, there were only 2 atherosclerotic plaques detected in FMF patients. These results may be attributable to our relatively young patient population. On the other hand, this is a cross-sectional study with a limited number of subjects; therefore, our results should be assessed cautiously. Our control subjects were enrolled from the hospital staff, which could also be thought to be a potential bias.
The MEFV mutations were found to be associated with the severity of inflammatory diseases. Homozygote M694V mutation is associated with a more severe disease course and risk for developing amyloidosis in FMF. The carrier rate of MEFV mutations reaches about 20% to 30% of the population in certain ethnic groups. Ongoing low-grade inflammation was shown not only in FMF patients but also in carriers of MEFV mutations (1). Further assessment of the effect of these mutations on the atherosclerotic process will provide more a accurate risk stratification for those who have these mutations. The role of impaired endothelial function and IMT of carotid arteries in detecting amyloidosis should also be evaluated in patients with FMF. Further investigations in larger samples are needed to establish the relationship between FMF and atherosclerosis.
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1. Touitou I. The spectrum of familial Mediterranean fever (FMF) mutations Eur J Hum Genet 2001;9:473-483.[CrossRef][Web of Science][Medline]2. Haskard DO. Accelerated atherosclerosis in inflammatory rheumatic diseases Scand J Rheumatol 2004;33:281-292.[CrossRef][Web of Science][Medline] 3. Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever Arthritis Rheum 1997;40:1879-1885.[Web of Science][Medline] 4. Lidar M, Scherrmann JM, Shinar Y, et al. Colchicine nonresponsiveness in familial Mediterranean fever: clinical, genetic, pharmacokinetic, and socioeconomic characterization Semin Arthritis Rheum 2004;33:273-282.[CrossRef][Web of Science][Medline] 5. Yan RT, Anderson TJ, Charbonneau F, et al. Relationship between carotid artery intima-media thickness and brachial artery flow-mediated dilation in middle-aged healthy men J Am Coll Cardiol 2005;45:1980-1986.[Abstract/Free Full Text] 6. Borhani NO, Mercuri M, Borhani PA, et al. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS)—a randomized controlled trial JAMA 1996;276:785-791.[Abstract/Free Full Text] 7. Langevitz P, Livneh A, Neumann L, et al. Prevalence of ischemic heart disease in patients with familial Mediterranean fever Isr Med Assoc J 2001;3:9-12.[Web of Science][Medline] 8. Sattar N, McCarey DW, Capell H, et al. Explaining how "high-grade" systemic inflammation accelerates vascular risk in rheumatoid arthritis Circulation 2003;16:2957-2963108.
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S. Ugurlu, E. Seyahi, F. Cetinkaya, F. Ozbakir, H. Balci, and H. Ozdogan
Intima-media thickening in patients with familial Mediterranean fever
Rheumatology,
August 1, 2009;
48(8):
911 - 915.
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