International Journal of Rheumatic Diseases 2014
ORIGINAL ARTICLE
Assessment of autonomic functions in children with familial Mediterranean fever by using heart rate variability measurements Kursat FIDANCI,1 Mustafa GULGUN,1 Erkan DEMIRKAYA,2,3 Cengizhan ACIKEL,3,4 Ayhan KILIC,1 Faysal GOK2 and Seza OZEN5 1
Department of Pediatric Cardiology, 2Department of Pediatric Rheumatology, 3FMF Arthritis Vasculitis and Orphan Disease Research in Pediatric Rheumatology (FAVOR), 4Department of Biostatistics, Gulhane Military Medical Faculty, and 5Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey
Abstract Aim: The aim of this study is to analyze possible autonomic nerve system alterations and assess the efficacy of heart rate variability (HRV) analysis in anticipation of cardiovascular risks in pediatric patients with familial Mediterranean fever (FMF). Method: In this study, cardiac autonomic functions were investigated in children with FMF by analyzing HRV and its other probable cardiac effects by echocardiography. We studied 70 pediatric patients with FMF and 50 healthy controls. Results: The time-domain parameters of HRV were compared between the FMF and control groups. SDNN (standard deviation of all NN intervals) was significantly decreased in patients with FMF as compared to control subjects. The other time-domain parameters of HRV and the frequency-domain parameters of HRV were similar in both groups. Frequency-dependent HRV parameters were similar in both groups, as were conventional echocardiographic parameters. Conclusion: HRV is a convenient and reliable technique for evaluation of autonomic functions. There are only a few studies on the assessment of autonomic functions by means of HRV in adult FMF patients but not in pediatric patients. Further studies are required to assess whether there is autonomic dysfunction in children with FMF. Key words: autonomic nerve system, familial Mediterranean fever, heart rate variability.
INTRODUCTION Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease characterized by recurrent attacks of serositis of the peritoneum, pleura, synovi-
Correspondence: Associate Professor Erkan Demirkaya, FMF Arthritis Vasculitis and Orphan Disease Research Center, Gulhane Military Medical Faculty, Institute of Health Sciences, 06018 Etlik, Ankara, Turkey. Email: [email protected]
um and rarely pericardium, often accompanied by fever.1 Cardiovascular events are the main reason for death in autoinflammatory diseases. In echocardiographic examinations for the detection of cardiovascular complications, a variety of functional, especially pericardial, abnormalities are observed.2,3 In addition, autoinflammatory diseases have potential effects on the cardiac autonomic nervous system (ANS). The most important of these, autonomic tone abnormalities, are associated with cardiovascular outcomes including life-threatening
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
K. Fidanci et al.
ventricular arrhythmias and sudden cardiac death (SCD).4 There are several studies that show the cardiovascular effects and autonomic dysfunction in autoinflammatory diseases.5–11 The clinical and subclinical cardiovascular effects of FMF have been shown in a few studies.5,12–14 Rozenbaum et al.15 reported abnormal autonomic activity in FMF similar to dysautonomia described in various rheumatic diseases. In a recent study, Canpolat et al.16 demonstrated the presence of autonomic dysfunction in FMF patients through heart rate variability (HRV) parameters. There are a few studies on the autonomic nervous system alterations possibly responsible for the cardiovascular effects of FMF; however, these studies do not include data pertinent to the pediatric age group.10,15–17 The best non-invasive method to assess the quantitative relationship between the ANS and the cardiovascular system is to measure HRV.18,19 HRV is defined as beat-by-beat R–R (interval between systole on electrocardiograph [ECG]) interval variability. A significant relationship has been reported between ANS and cardiovascular mortality, especially in cases of sudden cardiac death.18,19 Thus, HRV analysis has been used in many diseases, particularly diseases of the cardiovascular system, as a measure of cardiac autonomic tone.20,21 HRV is conveniently used in clinics due to the ease of calculation by computer systems.11 In this study, we evaluated the cardiac autonomic functions and possible cardiac effects of FMF in children by analysis of the HRV and echocardiography. We aimed to investigate possible ANS alterations and the efficacy of HRV analysis in prediction of cardiovascular risks in children with FMF. To the best of our knowledge, these parameters have not yet been reported in childhood FMF.
METHODS Patients/participants The study population included 70 consecutive FMF patients and 50 healthy control subjects. All FMF patients were diagnosed according to the clinical criteria outlined by Livneh et al.22 The control group consisted of 50 healthy volunteers comparable for age and gender. Patients with diabetes mellitus, hypertension, chronic renal failure, chronic liver disease, malignancy, amyloidosis, active infectious disease, cardiomyopathy, rhythm abnormalities and congenital or acquired heart disease or patients taking drugs that can influence the
2
ANS were excluded from the study. All patients were using regular colchicine therapy. Clinical and laboratory assessment of FMF patients were performed during an attack-free period or at least 10 days after an attack. A 12-lead surface ECG, 24-h ambulatory electrocardiographic monitorization (AECG) and transthoracic echocardiography were taken from each patient. The study protocol was approved by the institutional ethics committee. Informed written consent was obtained from each patient.
Echocardiography Images were obtained on a Siemens Acuson Sequoia C256 cardiac ultrasonographic scanner (Acuson, Mountain View, CA, USA), with 2.5- to 3.5-MHz transducers. Patients were in the left lateral decubitus position, resting comfortably. M-mode tracings were obtained at the level of the tips of the mitral leaflets in the parasternal long-axis position, and measurements of left ventricular end-systolic dimension (LVESD) and left ventricular end-diastolic dimension (LVEDD) were taken according to the recommendations of the American Society of Echocardiography.19 In M-mode echocardiography, ventricular septal and posterior wall thicknesses were measured at end-diastole through parasternal long-axis view. Left ventricular ejection fraction (EF) and fractional shortening (FS) were obtained using the Teichholz method.20
HRV Twenty-four hour Holter recordings were obtained using 12-channel analog recorders using the Rozinn Holter system (Rozinn, Cleveland, OH, USA). The time-domain HRV measures employed in our practice were as follows: 1 SDNN: standard deviation values of all normal sinus R–R intervals over 24 h; 2 SDANN: standard deviation values of all averaged normal sinus R–R intervals for each 5-min segment in the 24-h recordings; 3 RMSSD: root mean squares of successive differences between normal sinus R–R intervals; 4 HRV triangular index: ratios of number of all R–R intervals to height of the histogram created by charting all R–R intervals; 5 SNN50 count: numbers of R–R intervals exceeding 50 ms; and 6 PNN50: percentage of difference between adjacent normal R–R intervals that is greater than 50 ms computed over the entire 24-h ECG recording.
International Journal of Rheumatic Diseases 2014
Autonomic functions in children with FMF
Spectral analysis of HRV was obtained by summing powers of each frequency band: 1 high-frequency (HF) component (0.15–0.40 Hz); 2 low-frequency (LF) component (0.04–0.15 Hz); and 3 very-low-frequency (VLF) component (0–0.04 Hz). The LF/HF was calculated in all patients.20
Statistical analyses Statistical analyses were performed by using SPSS statistical software (version 15.0; SPSS Inc., Chicago, IL, USA). Distribution of continuous variables was evaluated by one-sample Kolmogorov–Smirnov test. As for descriptive statistics, mean standard deviation was used for normally distributed variables; and median (minimum-maximum) was used for non-normally distributed continuous variables. Categorical variables were presented as frequencies and percentages. For continuous variables, an independent sample t-test and Mann–Whitney U-test were used for independent samples comparisons. Chi-square test and Fischer’s exact tests were used for comparisons of categorical variables. Correlation analyses were performed by using the Pearson coefficient of correlation. A two-tailed P < 0.05 was considered statistically significant.
RESULTS The mean age of the participants in the study group (n = 70) was 11.14 3.53 years and in the control
group (n = 50) the mean age was 10.68 3.11 years. The female/male ratio was 27/70 in the study group and 20/50 in the control group. The duration of the disease was 46 9.2 months. None of the participants had any significant family history. The C-reactive protein (CRP) values were within normal limits in all patients (0–0.05 mg/L). According to baseline clinical and demographic characteristics, the patients with FMF and control subjects were similar with regard to age and gender (Table 1). All patients and controls were in sinus rhythm and had normal 12-lead ECG at rest. Holter recordings of patients and controls were negative for any kind of arrhythmias. The time-domain parameters of HRV were compared between the FMF and control groups. SDNN was significantly decreased in patients with FMF as compared to control subjects (P = 0.008; Table 2). The other timedomain parameters of HRV and the frequency-domain parameters of HRV were similar in both groups (P > 0.05; Table 2). Comparisons of the baseline echocardiographic values between patients and healthy controls are summarized in Table 3. There was no difference between the groups regarding LVEDD, LVESD, interventricular septum thickness diastolic or systolic, left ventricular posterior wall thickness diastolic or systolic, left atrium dimension, aortic dimension, ejection fraction or fractional shortening.
Table 1 Demographic and clinical features of patients and the controls Number of subjects Age (years) Male/female Min. heart rate (beats/min) Max. heart rate (beats/min) Mean heart rate (beats/min) Systolic BP (mmHg) Diastolic BP (mmHg) C-reactive protein (mg/L) Sedimentation rate (mm/h) Clinical manifestations Abdominal involvement, n (%) Arthritic involvement, n (%) Chest involvement, n (%) Fever, n (%) Duration of disease (months)
FMF (mean SD)
Control (mean SD)
P-value
70 11.14 3.536 27/43 45.90 6.538 144.29 11.846 83.61 13.509 104.52 11.44 65.68 11.58 0.42 0.69 12 8.58
50 10.68 3.107 20/30 46.46 8.942 137.42 12.444 85.00 14.971 102.46 11.38 66.24 11.38 0.31 0.18 8.59 5.87
0.910 0.642 0.874 0.890 0.003 0.656 0.628 0.088 0.546 0.654
52 (74) 13 (19) 12 (17) 67 (96) 46 9.2
– – – – –
– – – – –
BP, blood pressure; FMF, familial Mediterranean fever.
International Journal of Rheumatic Diseases 2014
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Table 2 Comparison of heart rate variability parameters between patients with FMF and healthy subjects FMF (n = 70) (mean SD) Time-domain parameters of HRV SDNN (ms) 131.14 SDANN (ms) 35.89 SDNN index 76.64 RMSSD (ms) 77.04 pNN50 (%) 29.91 Frequency-domain parameters of HRV 3277.78 TP (ms2) 1947.41 VLF (ms2) LF (ms2) 745.81 625.94 HF (ms2) 1.49 LF/HF (ms2/ms2)
Control (n = 50) (mean SD)
Test value
P-value
32.505 14.993 21.515 40.39 16.26
148.62 34.02 80.20 69.88 29.13
38.605 11.28 23.29 29.69 13.77
t Z Z Z
= = = = t=
2.684 0.333 0.655 0.948 0.276
0.008 0.739 0.513 0.343 0.783
1946.17 1139.21 541.65 507.06 0.91
3684.86 2151.18 847.67 686.00 1.62
1745.16 974.62 465.21 548.38 0.85
Z Z Z Z Z
= = = = =
1.373 1.469 1.538 0.506 1.208
0.170 0.142 0.124 0.613 0.227
t: t-test, Z: Mann–Whitney U-test. HF, high-frequency component; LF, low-frequency component; pNN50, the number of pairs of adjacent NN intervals differing by more than 50 ms divided by the total number of all NN intervals; RMSDD, the square root of the mean of the sum of the squares of differences between adjacent NN intervals; SDNN, standard deviations of all NN intervals; SDANN, standard deviation of the averages of NN intervals in all 5-min segments of the entire recording; TP, total power; VLF, very-low-frequency component.
Table 3 Comparison of echocardiographic parameters between patients with FMF and healthy subjects Parameters
FMF (n = 70) (mean SD)
LVEDD (mm) LVESD (mm) IVSd (mm) IVSs (mm) LVPWd (mm) LVPWs (mm) LAD (mm) AOD (mm) EF FS
37.50 22.42 6.08 9.77 6.53 9.38 22.55 19.81 71.47 40.03
5.13 3.75 1.39 3.27 1.66 3.27 4.07 3.24 4.63 4.09
Control (n = 50) (mean SD) 37.69 22.63 6.09 9.84 6.60 9.87 23.43 20.43 71.16 39.72
5.46 3.80 1.48 2.04 1.89 3.25 4.11 3.06 4.26 4.00
Test value
t t Z Z Z Z t Z
= = = = = = = = t= t=
0.198 0.307 0.075 0.032 0.048 0.887 1.157 1.001 0.375 0.423
P-value
0.843 0.760 0.940 0.974 0.962 0.375 0.250 0.317 0.708 0.673
t: t-test, Z: Mann–Whitney U-test. AOD, aortic dimension; EF, ejection fraction; FS, fractional shortening; IVSd, interventricular septum thickness diastolic; IVSs, interventricular septum thickness systolic; LAD, left atrium dimension; LVEDD, left ventricle end-diastolic diameter; LVESD, left ventricle end-sistolic diameter; LVPWd, left ventricular posterior wall thickness diastolic; LVPWs, left ventricular posterior wall thickness systolic.
DISCUSSION In our study, the SDNN value, one of the time-domain parameters of HRV calculated and analyzed by Holter software was significantly decreased in patients with FMF as compared to healthy controls. The frequencydomain parameters of HRV were similar in both groups, as were the echocardiographic parameters. Cardiovascular diseases are the leading causes of morbidity and mortality among patients with autoimmune diseases.23 In autoimmune diseases, conduction
4
disturbances and rhythm disorders are important manifestations of cardiac involvement in addition to accelerated atherosclerosis.24 FMF is also associated with conduction disturbances and rhythm abnormalities; however, there is no important evidence on this.25 One of the major causes of conduction abnormalities is believed to be the fluctuations in autonomic tone.18–26 ANS plays an important role in the regulation of cardiovascular functions. Several previous studies have investigated the association between cardiac indices of
International Journal of Rheumatic Diseases 2014
Autonomic functions in children with FMF
autonomic dysfunction and autoimmune diseases such as rheumatoid arthritis, systemic sclerosis, FMF, Behcßet’s disease and systemic lupus erythematosus (SLE).27–30 In 2002, Rozenbaum et al. studied 40 FMF patients and 25 healthy controls and found that FMF patients exhibit an abnormal cardiovascular reactivity, which is clinically occult, but can be detected on autonomic challenge. Pathological endpoints of vasodepressor or cardio-inhibitory reactions and orthostatic hypotension were observed in 17% of FMF patients and in none of the controls.15 In another study, 18.1% of the FMF patients developed symptoms of dysautonomia and abnormal cardiovascular reactivity scores when subjected to autonomic challenge by tilt table test.17 Nussinovitch et al.10 evaluated short-term HRV in 34 FMF patients and they found similar findings between FMF patients and healthy controls. Nussinovitch et al. later studied 40 FMF patients grouped as 20 patients without amyloidosis (uncomplicated), 10 with early amyloidosis and 10 with advanced amyloidosis. In the early amyloidosis group, only SDNN was significantly lower compared with controls.11 Progressive amyloidosis was associated with significantly lower SDNN, HRV triangular index, RMSSD, PNN50 and NN50, compared with the control group and the uncomplicated FMF patient group. They found abnormal HRV results mostly in patients with advanced amyloidosis. They concluded that amyloidosis of FMF, particularly at a progressive stage, is associated with HRV abnormalities suggestive of the presence of autonomic nervous system dysfunction. We excluded patients with FMF-amyloidosis because of the proven effects of amyloid accumulation on autonomic cardiac conduction. In our study, in contrast to the results of Nussinovitch et al., SDNN values were lower in the uncomplicated FMF patient group. However, these studies had the limitation of being based on shortterm recordings, as it has been shown that the reliability of the parameters of HRV is proportional to the recording time.31,32 In the literature, the first and only study made with long recording times (24-h Holter rhythm) was conducted by Canpolat et al.16 In this study, SDNN, SDANN, RMSDD, PNN50 and HF were decreased and LF and LF/HF ratio were increased in patients with FMF, as compared to the healthy control group, which was interpreted as evidence of cardiac autonomic dysfunction in FMF patients. Due to the controversial results of these studies and the absence of an assessment of pediatric age groups,
International Journal of Rheumatic Diseases 2014
we conducted our study on 70 children with uncomplicated FMF on regular colchicine and 50 healthy controls. We found decreased SDNN in accordance with Canpolat et al.; however, the other HRV parameters were normal in patients with FMF. The European Society of Cardiology guideline reports SDNN as the time-domain parameter that provides information about all HRV.20 Thus, decreased SDNN alone can be considered as evidence of dysautonomia.20,33,34 In our study, frequency-domain parameters of LF, HF and LF/HF were normal, possibly because these parameters are better suited for short-term rather than long-term recordings. We found normal values of RMSSD and PNN50, which represent vagal tone. Pediatric patients may have better preserved vagal tone as compared to adults. In addition, cardiac dysautonomia may be more evident in older patients due to the long-term history of FMF. In the study by Nussinovitch et al., Canpolat et al. and also in our study, the patients with FMF were on low-dose colchicine on a regular basis.10,16 It has been shown in vitro that colchicine has chronotropic cardiac effects.35 However, data is scarce about the cardiac effects of therapeutic doses of colchicine. In 2010, Kalkan et al. performed conventional, strain and tissue Doppler echocardiography in 23 FMF patients and 22 healthy controls. They did not observe any significant differences between the patient and control groups in terms of two-dimensional and M-mode echocardiography, as well as conventional Doppler and tissue Doppler velocities. They only found that left ventricular strain values were significantly lower in FMF patients than in controls.36 We also found similar conventional echocardiography values in FMF patients and controls. In these patients, although the disease seems to be controlled with colchicine, the dysautonomia detected with HRV studies suggests ongoing subclinical inflammation. This finding is in accordance with the findings of Duzova et al.37 who showed ongoing hidden inflammation despite appropriate medical treatment. To conclude, our study shows the presence of cardiac autonomic dysfunction in patients with FMF. It should be noted that autonomic dysfunction may pose a particular risk for cardiovascular complications, especially arrhythmias, in patients with FMF, even in the absence of cardiovascular symptoms. However, larger multicenter studies that include genetic markers and more specifically neuroimaging, are needed to clarify the extent of cardiovascular autonomic dysfunction in these patients.
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Limitation 37
However, Duzova et al. has already showed that subclinical inflammation continues during an attack-free period in FMF patients and serum amyloid A was the best marker of subclinical inflammation but we did not evaluate serum amyloid A levels. If we evaluate serum amyloid A levels, we could easily say subclinical inflammation continues.
AUTHOR CONTRIBUTIONS Study design: KF, AK, ED, SO; data collection: KF, MG; statistics: CA; manuscript preparation: KF, ED, FG.
CONFLICT OF INTEREST AND FUNDING There are no conflicts of interest or funding.
REFERENCES 1 Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 43, 227–53. 2 Calıskan M, Gullu H, Yılmaz S et al. (2007) Impaired coronary microvascular function in familial Mediterranean fever. Atherosclerosis 195, e161–7. 3 Dabestani A, Larry MN, Child JS, Krivokapich J, Schwabe AD (1982) Pericardial disease in familial Mediterranean fever: an echocardiographic study. Chest 81, 592–5. 4 Lazzerini PE, Capecchi PL, Guideri F, Acampa M, Galeazzi M, Laghi Pasini F (2006) Connective tissue diseases and cardiac rhythm disorders: an overview. Autoimmun Rev 5, 306–13. 5 Akcay A, Acar G, Sayarlioglu M et al. (2009) QT dispersion and transmural dispersion of repolarization in patients with familial Mediterranean fever. Mod Rheumatol 19, 550–5. 6 Kaya EB, Yorgun H, Akdogan A et al. (2009) Heart-rate recovery index is impaired in Behcet’s disease. Tex Heart Inst J 36, 282–6. 7 Ardic I, Kaya MG, Yarlioglues M et al. (2011) Assessment of heart rate recovery index in patients with familial Mediterranean fever. Rheumatol Int 31, 121–5. 8 Aydemir M, Yazisiz V, Basarici I et al. (2010) Cardiac autonomic profile in rheumatoid arthritis and systemic lupus erythematosus. Lupus 19, 255–61. 9 Kaya EB, Okutucu S, Aksoy H et al. (2010) Evaluation of cardiac autonomic functions in patients with ankylosing spondylitis via heart rate recovery and heart rate variability. Clin Res Cardiol 99, 803–8. 10 Nussinovitch N, Livneh A, Katz K et al. (2010) QT dispersion in uncomplicated familial Mediterranean fever. Clin Rheumatol 29, 1353–6.
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11 Nussinovitch N, Livneh A, Katz K et al. (2011) Heart rate variability in familial Mediterranean fever. Rheumatol Int 31 (1), 39–43. 12 Bilginer Y, Ozaltin F, Basaran C et al. (2008) Evaluation of intima media thickness of the common and internal carotid arteries with inflammatory markers in familial Mediterranean fever as possible predictors for atherosclerosis. Rheumatol Int 28, 1211–6. 13 Sarı I, Arıcan O, Can G et al. (2008) Assessment of aortic stiffness and ventricular functions in familial Mediterranean fever. Anadolu Kardiyol Derg 8, 271–8. 14 Caliskan M, Gullu H, Yilmaz S et al. (2007) Impaired coronary microvascular function in familial Mediterranean fever. Atherosclerosis 195, 161–7. 15 Rozenbaum M, Naschitz JE, Yudashkin M et al. (2002) Cardiovascular autonomic dysfunction in familial Mediterranean fever. J Rheumatol 29, 987–9. 16 Canpolat U, Dural M, Aytemir K et al. (2012) Evaluation of various cardiac autonomic indices in patients with familial Mediterranean fever on colchicine treatment. Auton Neurosci 167, 70–4. 17 Rozenbaum M, Naschitz JE, Yudashkin M et al. (2004) Cardiovascular reactivity score for the assessment of dysautonomia in familial Mediterranean fever. Rheumatol Int 24, 147–52. 18 Akselrod S, Gordon D, Madwed JB, Snidman NC, Shannon DC, Cohen RJ (1985) Hemodynamic regulation: investigation by spectral analysis. Am J Physiol 249, 867–75. 19 Lombardi F, Malliani A, Pagani M, Cerruti S (1996) Heart rate variability and sympatovagal modulation. Cardivasc Res 32, 208–16. 20 Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996) Heart rate variability: standards of measurements, physiological interpretation and clinical use. Circulation 93, 1043–65. 21 Malik M (1998) Heart rate variability. Curr Opin Cardiol 13, 36–44. 22 Livneh A, Langevitz P, Zemer D et al. (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40, 1879–85. 23 Knockaert DC (2007) Cardiac involvement in systemic inflammatory diseases. Eur Heart J 28, 1797–804. 24 Abu-Shakra M, Urowitz MB, Gladman DD, Gough J (1995) Mortality studies in systemic lupus erythematosus. Results from a single center. I. Causes of death. J Rheumatol 22, 1259–64. 25 Gale A, Levin ME (1963) Pericarditis and auricular fibrillation. Occurrence in familial mediterranean fever. Arch Intern Med 112, 234–41. 26 Schwartz PJ, Priori SG (1990) Sympathetic nervous system and cardiac arrhythmias. In: Zipes DP, Jalife J (eds) Cardiac Electrophysiology. From Cell to Bedside, pp 330–43. WB Sounders, Philadelphia, PA, USA.
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27 Sloan RP, Shapiro PA, Bigger JT Jr, Bagiella E, Steinman RC, Gorman JM (1994) Cardiac autonomic control and hostility in healty subjects. Am J Cardiol 74, 298–300. 28 Iellamo F, Legramente M, Massaro M, Raimondi G, Galante A (2000) Effects of a residential exercise training on baroreflex sensivity and heart rate variability in patients with coronary artery disease. Circulation 102, 2588–92. 29 Evrengul H, Dursunoglu D, Cobankara V et al. (2004) Heart rate variability in patients with rheumatoid arthritis. Rheumatol Int 24, 198–202. 30 Laversuch CJ, Seo H, Modarres H, Collins DA, McKenna W, Bourke BE (1997) Reduction in heart rate variability in patients with systemic lupus erythematosus. J Rheumatol 24, 1540–4. 31 Malik M, Farrell T, Camm AJ (1990) Circadian rhythm of heart rate variability after acute myocardial infarction and its influence on the prognostic value of heart rate variability. Am J Cardiol 66, 1049–54.
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32 Smith S (1982) Reduced sinus arrhythmia in diabetic autonomic neuropathy: diagnostic value of an age related normal range. Br Med J 285, 1599–601. 33 Malik M, Farrell T, Cripps T, Camm AJ (1989) Heart rate variability in relation to prognosis after myocardial infarction: selection of optimal processing techniques. Eur Heart J 10, 1060–74. 34 Stein PK, Bosner MS, Kleiger RE, Conger BM (1994) Heart rate variability: a measure of cardiac autonomic tone. Am Heart J 127, 1376–81. 35 Klein I (1983) Colchicine stimulates the rate of contraction of heart cells in culture. Cardiovasc Res 17, 459–65. 36 Kalkan GY, Bayram NA, Erten S et al. (2010) Evaluation of left ventricle function by strain imaging in patients with Familial Mediterranean Fever. Echocardiography 27, 1056–60. 37 Duzova A, Bakkaloglu A, Besbas N et al. (2003) Role of ASAA in monitoring subclinical inflammation and in colchicine dosage in familial Mediterranean fever. Clin Exp Rheumatol 21, 509–14.
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ORIGINAL ARTICLE
Assessment of autonomic functions in children with familial Mediterranean fever by using heart rate variability measurements Kursat FIDANCI,1 Mustafa GULGUN,1 Erkan DEMIRKAYA,2,3 Cengizhan ACIKEL,3,4 Ayhan KILIC,1 Faysal GOK2 and Seza OZEN5 1
Department of Pediatric Cardiology, 2Department of Pediatric Rheumatology, 3FMF Arthritis Vasculitis and Orphan Disease Research in Pediatric Rheumatology (FAVOR), 4Department of Biostatistics, Gulhane Military Medical Faculty, and 5Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey
Abstract Aim: The aim of this study is to analyze possible autonomic nerve system alterations and assess the efficacy of heart rate variability (HRV) analysis in anticipation of cardiovascular risks in pediatric patients with familial Mediterranean fever (FMF). Method: In this study, cardiac autonomic functions were investigated in children with FMF by analyzing HRV and its other probable cardiac effects by echocardiography. We studied 70 pediatric patients with FMF and 50 healthy controls. Results: The time-domain parameters of HRV were compared between the FMF and control groups. SDNN (standard deviation of all NN intervals) was significantly decreased in patients with FMF as compared to control subjects. The other time-domain parameters of HRV and the frequency-domain parameters of HRV were similar in both groups. Frequency-dependent HRV parameters were similar in both groups, as were conventional echocardiographic parameters. Conclusion: HRV is a convenient and reliable technique for evaluation of autonomic functions. There are only a few studies on the assessment of autonomic functions by means of HRV in adult FMF patients but not in pediatric patients. Further studies are required to assess whether there is autonomic dysfunction in children with FMF. Key words: autonomic nerve system, familial Mediterranean fever, heart rate variability.
INTRODUCTION Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease characterized by recurrent attacks of serositis of the peritoneum, pleura, synovi-
Correspondence: Associate Professor Erkan Demirkaya, FMF Arthritis Vasculitis and Orphan Disease Research Center, Gulhane Military Medical Faculty, Institute of Health Sciences, 06018 Etlik, Ankara, Turkey. Email: [email protected]
um and rarely pericardium, often accompanied by fever.1 Cardiovascular events are the main reason for death in autoinflammatory diseases. In echocardiographic examinations for the detection of cardiovascular complications, a variety of functional, especially pericardial, abnormalities are observed.2,3 In addition, autoinflammatory diseases have potential effects on the cardiac autonomic nervous system (ANS). The most important of these, autonomic tone abnormalities, are associated with cardiovascular outcomes including life-threatening
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
K. Fidanci et al.
ventricular arrhythmias and sudden cardiac death (SCD).4 There are several studies that show the cardiovascular effects and autonomic dysfunction in autoinflammatory diseases.5–11 The clinical and subclinical cardiovascular effects of FMF have been shown in a few studies.5,12–14 Rozenbaum et al.15 reported abnormal autonomic activity in FMF similar to dysautonomia described in various rheumatic diseases. In a recent study, Canpolat et al.16 demonstrated the presence of autonomic dysfunction in FMF patients through heart rate variability (HRV) parameters. There are a few studies on the autonomic nervous system alterations possibly responsible for the cardiovascular effects of FMF; however, these studies do not include data pertinent to the pediatric age group.10,15–17 The best non-invasive method to assess the quantitative relationship between the ANS and the cardiovascular system is to measure HRV.18,19 HRV is defined as beat-by-beat R–R (interval between systole on electrocardiograph [ECG]) interval variability. A significant relationship has been reported between ANS and cardiovascular mortality, especially in cases of sudden cardiac death.18,19 Thus, HRV analysis has been used in many diseases, particularly diseases of the cardiovascular system, as a measure of cardiac autonomic tone.20,21 HRV is conveniently used in clinics due to the ease of calculation by computer systems.11 In this study, we evaluated the cardiac autonomic functions and possible cardiac effects of FMF in children by analysis of the HRV and echocardiography. We aimed to investigate possible ANS alterations and the efficacy of HRV analysis in prediction of cardiovascular risks in children with FMF. To the best of our knowledge, these parameters have not yet been reported in childhood FMF.
METHODS Patients/participants The study population included 70 consecutive FMF patients and 50 healthy control subjects. All FMF patients were diagnosed according to the clinical criteria outlined by Livneh et al.22 The control group consisted of 50 healthy volunteers comparable for age and gender. Patients with diabetes mellitus, hypertension, chronic renal failure, chronic liver disease, malignancy, amyloidosis, active infectious disease, cardiomyopathy, rhythm abnormalities and congenital or acquired heart disease or patients taking drugs that can influence the
2
ANS were excluded from the study. All patients were using regular colchicine therapy. Clinical and laboratory assessment of FMF patients were performed during an attack-free period or at least 10 days after an attack. A 12-lead surface ECG, 24-h ambulatory electrocardiographic monitorization (AECG) and transthoracic echocardiography were taken from each patient. The study protocol was approved by the institutional ethics committee. Informed written consent was obtained from each patient.
Echocardiography Images were obtained on a Siemens Acuson Sequoia C256 cardiac ultrasonographic scanner (Acuson, Mountain View, CA, USA), with 2.5- to 3.5-MHz transducers. Patients were in the left lateral decubitus position, resting comfortably. M-mode tracings were obtained at the level of the tips of the mitral leaflets in the parasternal long-axis position, and measurements of left ventricular end-systolic dimension (LVESD) and left ventricular end-diastolic dimension (LVEDD) were taken according to the recommendations of the American Society of Echocardiography.19 In M-mode echocardiography, ventricular septal and posterior wall thicknesses were measured at end-diastole through parasternal long-axis view. Left ventricular ejection fraction (EF) and fractional shortening (FS) were obtained using the Teichholz method.20
HRV Twenty-four hour Holter recordings were obtained using 12-channel analog recorders using the Rozinn Holter system (Rozinn, Cleveland, OH, USA). The time-domain HRV measures employed in our practice were as follows: 1 SDNN: standard deviation values of all normal sinus R–R intervals over 24 h; 2 SDANN: standard deviation values of all averaged normal sinus R–R intervals for each 5-min segment in the 24-h recordings; 3 RMSSD: root mean squares of successive differences between normal sinus R–R intervals; 4 HRV triangular index: ratios of number of all R–R intervals to height of the histogram created by charting all R–R intervals; 5 SNN50 count: numbers of R–R intervals exceeding 50 ms; and 6 PNN50: percentage of difference between adjacent normal R–R intervals that is greater than 50 ms computed over the entire 24-h ECG recording.
International Journal of Rheumatic Diseases 2014
Autonomic functions in children with FMF
Spectral analysis of HRV was obtained by summing powers of each frequency band: 1 high-frequency (HF) component (0.15–0.40 Hz); 2 low-frequency (LF) component (0.04–0.15 Hz); and 3 very-low-frequency (VLF) component (0–0.04 Hz). The LF/HF was calculated in all patients.20
Statistical analyses Statistical analyses were performed by using SPSS statistical software (version 15.0; SPSS Inc., Chicago, IL, USA). Distribution of continuous variables was evaluated by one-sample Kolmogorov–Smirnov test. As for descriptive statistics, mean standard deviation was used for normally distributed variables; and median (minimum-maximum) was used for non-normally distributed continuous variables. Categorical variables were presented as frequencies and percentages. For continuous variables, an independent sample t-test and Mann–Whitney U-test were used for independent samples comparisons. Chi-square test and Fischer’s exact tests were used for comparisons of categorical variables. Correlation analyses were performed by using the Pearson coefficient of correlation. A two-tailed P < 0.05 was considered statistically significant.
RESULTS The mean age of the participants in the study group (n = 70) was 11.14 3.53 years and in the control
group (n = 50) the mean age was 10.68 3.11 years. The female/male ratio was 27/70 in the study group and 20/50 in the control group. The duration of the disease was 46 9.2 months. None of the participants had any significant family history. The C-reactive protein (CRP) values were within normal limits in all patients (0–0.05 mg/L). According to baseline clinical and demographic characteristics, the patients with FMF and control subjects were similar with regard to age and gender (Table 1). All patients and controls were in sinus rhythm and had normal 12-lead ECG at rest. Holter recordings of patients and controls were negative for any kind of arrhythmias. The time-domain parameters of HRV were compared between the FMF and control groups. SDNN was significantly decreased in patients with FMF as compared to control subjects (P = 0.008; Table 2). The other timedomain parameters of HRV and the frequency-domain parameters of HRV were similar in both groups (P > 0.05; Table 2). Comparisons of the baseline echocardiographic values between patients and healthy controls are summarized in Table 3. There was no difference between the groups regarding LVEDD, LVESD, interventricular septum thickness diastolic or systolic, left ventricular posterior wall thickness diastolic or systolic, left atrium dimension, aortic dimension, ejection fraction or fractional shortening.
Table 1 Demographic and clinical features of patients and the controls Number of subjects Age (years) Male/female Min. heart rate (beats/min) Max. heart rate (beats/min) Mean heart rate (beats/min) Systolic BP (mmHg) Diastolic BP (mmHg) C-reactive protein (mg/L) Sedimentation rate (mm/h) Clinical manifestations Abdominal involvement, n (%) Arthritic involvement, n (%) Chest involvement, n (%) Fever, n (%) Duration of disease (months)
FMF (mean SD)
Control (mean SD)
P-value
70 11.14 3.536 27/43 45.90 6.538 144.29 11.846 83.61 13.509 104.52 11.44 65.68 11.58 0.42 0.69 12 8.58
50 10.68 3.107 20/30 46.46 8.942 137.42 12.444 85.00 14.971 102.46 11.38 66.24 11.38 0.31 0.18 8.59 5.87
0.910 0.642 0.874 0.890 0.003 0.656 0.628 0.088 0.546 0.654
52 (74) 13 (19) 12 (17) 67 (96) 46 9.2
– – – – –
– – – – –
BP, blood pressure; FMF, familial Mediterranean fever.
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Table 2 Comparison of heart rate variability parameters between patients with FMF and healthy subjects FMF (n = 70) (mean SD) Time-domain parameters of HRV SDNN (ms) 131.14 SDANN (ms) 35.89 SDNN index 76.64 RMSSD (ms) 77.04 pNN50 (%) 29.91 Frequency-domain parameters of HRV 3277.78 TP (ms2) 1947.41 VLF (ms2) LF (ms2) 745.81 625.94 HF (ms2) 1.49 LF/HF (ms2/ms2)
Control (n = 50) (mean SD)
Test value
P-value
32.505 14.993 21.515 40.39 16.26
148.62 34.02 80.20 69.88 29.13
38.605 11.28 23.29 29.69 13.77
t Z Z Z
= = = = t=
2.684 0.333 0.655 0.948 0.276
0.008 0.739 0.513 0.343 0.783
1946.17 1139.21 541.65 507.06 0.91
3684.86 2151.18 847.67 686.00 1.62
1745.16 974.62 465.21 548.38 0.85
Z Z Z Z Z
= = = = =
1.373 1.469 1.538 0.506 1.208
0.170 0.142 0.124 0.613 0.227
t: t-test, Z: Mann–Whitney U-test. HF, high-frequency component; LF, low-frequency component; pNN50, the number of pairs of adjacent NN intervals differing by more than 50 ms divided by the total number of all NN intervals; RMSDD, the square root of the mean of the sum of the squares of differences between adjacent NN intervals; SDNN, standard deviations of all NN intervals; SDANN, standard deviation of the averages of NN intervals in all 5-min segments of the entire recording; TP, total power; VLF, very-low-frequency component.
Table 3 Comparison of echocardiographic parameters between patients with FMF and healthy subjects Parameters
FMF (n = 70) (mean SD)
LVEDD (mm) LVESD (mm) IVSd (mm) IVSs (mm) LVPWd (mm) LVPWs (mm) LAD (mm) AOD (mm) EF FS
37.50 22.42 6.08 9.77 6.53 9.38 22.55 19.81 71.47 40.03
5.13 3.75 1.39 3.27 1.66 3.27 4.07 3.24 4.63 4.09
Control (n = 50) (mean SD) 37.69 22.63 6.09 9.84 6.60 9.87 23.43 20.43 71.16 39.72
5.46 3.80 1.48 2.04 1.89 3.25 4.11 3.06 4.26 4.00
Test value
t t Z Z Z Z t Z
= = = = = = = = t= t=
0.198 0.307 0.075 0.032 0.048 0.887 1.157 1.001 0.375 0.423
P-value
0.843 0.760 0.940 0.974 0.962 0.375 0.250 0.317 0.708 0.673
t: t-test, Z: Mann–Whitney U-test. AOD, aortic dimension; EF, ejection fraction; FS, fractional shortening; IVSd, interventricular septum thickness diastolic; IVSs, interventricular septum thickness systolic; LAD, left atrium dimension; LVEDD, left ventricle end-diastolic diameter; LVESD, left ventricle end-sistolic diameter; LVPWd, left ventricular posterior wall thickness diastolic; LVPWs, left ventricular posterior wall thickness systolic.
DISCUSSION In our study, the SDNN value, one of the time-domain parameters of HRV calculated and analyzed by Holter software was significantly decreased in patients with FMF as compared to healthy controls. The frequencydomain parameters of HRV were similar in both groups, as were the echocardiographic parameters. Cardiovascular diseases are the leading causes of morbidity and mortality among patients with autoimmune diseases.23 In autoimmune diseases, conduction
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disturbances and rhythm disorders are important manifestations of cardiac involvement in addition to accelerated atherosclerosis.24 FMF is also associated with conduction disturbances and rhythm abnormalities; however, there is no important evidence on this.25 One of the major causes of conduction abnormalities is believed to be the fluctuations in autonomic tone.18–26 ANS plays an important role in the regulation of cardiovascular functions. Several previous studies have investigated the association between cardiac indices of
International Journal of Rheumatic Diseases 2014
Autonomic functions in children with FMF
autonomic dysfunction and autoimmune diseases such as rheumatoid arthritis, systemic sclerosis, FMF, Behcßet’s disease and systemic lupus erythematosus (SLE).27–30 In 2002, Rozenbaum et al. studied 40 FMF patients and 25 healthy controls and found that FMF patients exhibit an abnormal cardiovascular reactivity, which is clinically occult, but can be detected on autonomic challenge. Pathological endpoints of vasodepressor or cardio-inhibitory reactions and orthostatic hypotension were observed in 17% of FMF patients and in none of the controls.15 In another study, 18.1% of the FMF patients developed symptoms of dysautonomia and abnormal cardiovascular reactivity scores when subjected to autonomic challenge by tilt table test.17 Nussinovitch et al.10 evaluated short-term HRV in 34 FMF patients and they found similar findings between FMF patients and healthy controls. Nussinovitch et al. later studied 40 FMF patients grouped as 20 patients without amyloidosis (uncomplicated), 10 with early amyloidosis and 10 with advanced amyloidosis. In the early amyloidosis group, only SDNN was significantly lower compared with controls.11 Progressive amyloidosis was associated with significantly lower SDNN, HRV triangular index, RMSSD, PNN50 and NN50, compared with the control group and the uncomplicated FMF patient group. They found abnormal HRV results mostly in patients with advanced amyloidosis. They concluded that amyloidosis of FMF, particularly at a progressive stage, is associated with HRV abnormalities suggestive of the presence of autonomic nervous system dysfunction. We excluded patients with FMF-amyloidosis because of the proven effects of amyloid accumulation on autonomic cardiac conduction. In our study, in contrast to the results of Nussinovitch et al., SDNN values were lower in the uncomplicated FMF patient group. However, these studies had the limitation of being based on shortterm recordings, as it has been shown that the reliability of the parameters of HRV is proportional to the recording time.31,32 In the literature, the first and only study made with long recording times (24-h Holter rhythm) was conducted by Canpolat et al.16 In this study, SDNN, SDANN, RMSDD, PNN50 and HF were decreased and LF and LF/HF ratio were increased in patients with FMF, as compared to the healthy control group, which was interpreted as evidence of cardiac autonomic dysfunction in FMF patients. Due to the controversial results of these studies and the absence of an assessment of pediatric age groups,
International Journal of Rheumatic Diseases 2014
we conducted our study on 70 children with uncomplicated FMF on regular colchicine and 50 healthy controls. We found decreased SDNN in accordance with Canpolat et al.; however, the other HRV parameters were normal in patients with FMF. The European Society of Cardiology guideline reports SDNN as the time-domain parameter that provides information about all HRV.20 Thus, decreased SDNN alone can be considered as evidence of dysautonomia.20,33,34 In our study, frequency-domain parameters of LF, HF and LF/HF were normal, possibly because these parameters are better suited for short-term rather than long-term recordings. We found normal values of RMSSD and PNN50, which represent vagal tone. Pediatric patients may have better preserved vagal tone as compared to adults. In addition, cardiac dysautonomia may be more evident in older patients due to the long-term history of FMF. In the study by Nussinovitch et al., Canpolat et al. and also in our study, the patients with FMF were on low-dose colchicine on a regular basis.10,16 It has been shown in vitro that colchicine has chronotropic cardiac effects.35 However, data is scarce about the cardiac effects of therapeutic doses of colchicine. In 2010, Kalkan et al. performed conventional, strain and tissue Doppler echocardiography in 23 FMF patients and 22 healthy controls. They did not observe any significant differences between the patient and control groups in terms of two-dimensional and M-mode echocardiography, as well as conventional Doppler and tissue Doppler velocities. They only found that left ventricular strain values were significantly lower in FMF patients than in controls.36 We also found similar conventional echocardiography values in FMF patients and controls. In these patients, although the disease seems to be controlled with colchicine, the dysautonomia detected with HRV studies suggests ongoing subclinical inflammation. This finding is in accordance with the findings of Duzova et al.37 who showed ongoing hidden inflammation despite appropriate medical treatment. To conclude, our study shows the presence of cardiac autonomic dysfunction in patients with FMF. It should be noted that autonomic dysfunction may pose a particular risk for cardiovascular complications, especially arrhythmias, in patients with FMF, even in the absence of cardiovascular symptoms. However, larger multicenter studies that include genetic markers and more specifically neuroimaging, are needed to clarify the extent of cardiovascular autonomic dysfunction in these patients.
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Limitation 37
However, Duzova et al. has already showed that subclinical inflammation continues during an attack-free period in FMF patients and serum amyloid A was the best marker of subclinical inflammation but we did not evaluate serum amyloid A levels. If we evaluate serum amyloid A levels, we could easily say subclinical inflammation continues.
AUTHOR CONTRIBUTIONS Study design: KF, AK, ED, SO; data collection: KF, MG; statistics: CA; manuscript preparation: KF, ED, FG.
CONFLICT OF INTEREST AND FUNDING There are no conflicts of interest or funding.
REFERENCES 1 Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 43, 227–53. 2 Calıskan M, Gullu H, Yılmaz S et al. (2007) Impaired coronary microvascular function in familial Mediterranean fever. Atherosclerosis 195, e161–7. 3 Dabestani A, Larry MN, Child JS, Krivokapich J, Schwabe AD (1982) Pericardial disease in familial Mediterranean fever: an echocardiographic study. Chest 81, 592–5. 4 Lazzerini PE, Capecchi PL, Guideri F, Acampa M, Galeazzi M, Laghi Pasini F (2006) Connective tissue diseases and cardiac rhythm disorders: an overview. Autoimmun Rev 5, 306–13. 5 Akcay A, Acar G, Sayarlioglu M et al. (2009) QT dispersion and transmural dispersion of repolarization in patients with familial Mediterranean fever. Mod Rheumatol 19, 550–5. 6 Kaya EB, Yorgun H, Akdogan A et al. (2009) Heart-rate recovery index is impaired in Behcet’s disease. Tex Heart Inst J 36, 282–6. 7 Ardic I, Kaya MG, Yarlioglues M et al. (2011) Assessment of heart rate recovery index in patients with familial Mediterranean fever. Rheumatol Int 31, 121–5. 8 Aydemir M, Yazisiz V, Basarici I et al. (2010) Cardiac autonomic profile in rheumatoid arthritis and systemic lupus erythematosus. Lupus 19, 255–61. 9 Kaya EB, Okutucu S, Aksoy H et al. (2010) Evaluation of cardiac autonomic functions in patients with ankylosing spondylitis via heart rate recovery and heart rate variability. Clin Res Cardiol 99, 803–8. 10 Nussinovitch N, Livneh A, Katz K et al. (2010) QT dispersion in uncomplicated familial Mediterranean fever. Clin Rheumatol 29, 1353–6.
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11 Nussinovitch N, Livneh A, Katz K et al. (2011) Heart rate variability in familial Mediterranean fever. Rheumatol Int 31 (1), 39–43. 12 Bilginer Y, Ozaltin F, Basaran C et al. (2008) Evaluation of intima media thickness of the common and internal carotid arteries with inflammatory markers in familial Mediterranean fever as possible predictors for atherosclerosis. Rheumatol Int 28, 1211–6. 13 Sarı I, Arıcan O, Can G et al. (2008) Assessment of aortic stiffness and ventricular functions in familial Mediterranean fever. Anadolu Kardiyol Derg 8, 271–8. 14 Caliskan M, Gullu H, Yilmaz S et al. (2007) Impaired coronary microvascular function in familial Mediterranean fever. Atherosclerosis 195, 161–7. 15 Rozenbaum M, Naschitz JE, Yudashkin M et al. (2002) Cardiovascular autonomic dysfunction in familial Mediterranean fever. J Rheumatol 29, 987–9. 16 Canpolat U, Dural M, Aytemir K et al. (2012) Evaluation of various cardiac autonomic indices in patients with familial Mediterranean fever on colchicine treatment. Auton Neurosci 167, 70–4. 17 Rozenbaum M, Naschitz JE, Yudashkin M et al. (2004) Cardiovascular reactivity score for the assessment of dysautonomia in familial Mediterranean fever. Rheumatol Int 24, 147–52. 18 Akselrod S, Gordon D, Madwed JB, Snidman NC, Shannon DC, Cohen RJ (1985) Hemodynamic regulation: investigation by spectral analysis. Am J Physiol 249, 867–75. 19 Lombardi F, Malliani A, Pagani M, Cerruti S (1996) Heart rate variability and sympatovagal modulation. Cardivasc Res 32, 208–16. 20 Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996) Heart rate variability: standards of measurements, physiological interpretation and clinical use. Circulation 93, 1043–65. 21 Malik M (1998) Heart rate variability. Curr Opin Cardiol 13, 36–44. 22 Livneh A, Langevitz P, Zemer D et al. (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40, 1879–85. 23 Knockaert DC (2007) Cardiac involvement in systemic inflammatory diseases. Eur Heart J 28, 1797–804. 24 Abu-Shakra M, Urowitz MB, Gladman DD, Gough J (1995) Mortality studies in systemic lupus erythematosus. Results from a single center. I. Causes of death. J Rheumatol 22, 1259–64. 25 Gale A, Levin ME (1963) Pericarditis and auricular fibrillation. Occurrence in familial mediterranean fever. Arch Intern Med 112, 234–41. 26 Schwartz PJ, Priori SG (1990) Sympathetic nervous system and cardiac arrhythmias. In: Zipes DP, Jalife J (eds) Cardiac Electrophysiology. From Cell to Bedside, pp 330–43. WB Sounders, Philadelphia, PA, USA.
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27 Sloan RP, Shapiro PA, Bigger JT Jr, Bagiella E, Steinman RC, Gorman JM (1994) Cardiac autonomic control and hostility in healty subjects. Am J Cardiol 74, 298–300. 28 Iellamo F, Legramente M, Massaro M, Raimondi G, Galante A (2000) Effects of a residential exercise training on baroreflex sensivity and heart rate variability in patients with coronary artery disease. Circulation 102, 2588–92. 29 Evrengul H, Dursunoglu D, Cobankara V et al. (2004) Heart rate variability in patients with rheumatoid arthritis. Rheumatol Int 24, 198–202. 30 Laversuch CJ, Seo H, Modarres H, Collins DA, McKenna W, Bourke BE (1997) Reduction in heart rate variability in patients with systemic lupus erythematosus. J Rheumatol 24, 1540–4. 31 Malik M, Farrell T, Camm AJ (1990) Circadian rhythm of heart rate variability after acute myocardial infarction and its influence on the prognostic value of heart rate variability. Am J Cardiol 66, 1049–54.
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32 Smith S (1982) Reduced sinus arrhythmia in diabetic autonomic neuropathy: diagnostic value of an age related normal range. Br Med J 285, 1599–601. 33 Malik M, Farrell T, Cripps T, Camm AJ (1989) Heart rate variability in relation to prognosis after myocardial infarction: selection of optimal processing techniques. Eur Heart J 10, 1060–74. 34 Stein PK, Bosner MS, Kleiger RE, Conger BM (1994) Heart rate variability: a measure of cardiac autonomic tone. Am Heart J 127, 1376–81. 35 Klein I (1983) Colchicine stimulates the rate of contraction of heart cells in culture. Cardiovasc Res 17, 459–65. 36 Kalkan GY, Bayram NA, Erten S et al. (2010) Evaluation of left ventricle function by strain imaging in patients with Familial Mediterranean Fever. Echocardiography 27, 1056–60. 37 Duzova A, Bakkaloglu A, Besbas N et al. (2003) Role of ASAA in monitoring subclinical inflammation and in colchicine dosage in familial Mediterranean fever. Clin Exp Rheumatol 21, 509–14.
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