Clin Rheumatol (2011) 30:1347–1351 DOI 10.1007/s10067-011-1759-5
ORIGINAL ARTICLE
Normal autonomic nervous system responses in uncomplicated familial Mediterranean fever: a comparative case–control study Udi Nussinovitch & Avi Livneh & Keren Kaminer & Pnina Langevitz & Olga Feld & Moshe Nussinovitch & Benjamin Volovitz & Merav Lidar & Naomi Nussinovitch
Received: 14 February 2011 / Accepted: 17 April 2011 / Published online: 4 May 2011 # Clinical Rheumatology 2011
Abstract There is a paucity of knowledge regarding the autonomic nervous system function in patients with familial Mediterranean fever (FMF). Therefore, our aim was to evaluate autonomic responses in patients with FMF using complementary tests. The study groups included 33 patients with uncomplicated FMF and 39 control subjects. Autonomic function was evaluated by measuring responses to metronomUdi Nussinovitch and Avi Livneh contributed equally to this paper. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. U. Nussinovitch (*) The Heller Institute of Medical Research, and Department of Medicine F, Sheba Medical Center, Tel Hashomer, Israel 52621 e-mail:
[email protected] A. Livneh : P. Langevitz : O. Feld : M. Lidar The Heller Institute of Medical Research, Chaim Sheba Medical Center, Tel Hashomer, Israel A. Livneh : P. Langevitz : O. Feld : M. Lidar Department of Internal Medicine F, Chaim Sheba Medical Center, Tel Hashomer, Israel U. Nussinovitch : A. Livneh : K. Kaminer : P. Langevitz : O. Feld : M. Nussinovitch : B. Volovitz : M. Lidar Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel M. Nussinovitch : B. Volovitz Department of Pediatrics C, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel N. Nussinovitch Hypertension Unit and Department of Internal Medicine D, Sheba Medical Center, Tel Hashomer, Israel
ic breathing, the Valsalva maneuver, and the Ewing maneuver. Autonomic parameters were computed from electrocardiograms with designated computer software. There were no statistically significant differences in any of the measured parameters of autonomic function between the patient and control group. The measured autonomic parameters of both groups were similar to those previously reported in healthy individuals. In conclusion, patients with FMF who did not develop amyloidosis due to continuous colchicine treatment appeared to have normal autonomic function, as reflected by the normal response to physiological autonomic stimuli. Keywords Autonomic nervous system . Ewing maneuver . Familial Mediterranean fever . Heart rate variability . Dysautonomia
Introduction Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent self-limited attacks of fever and sterile polyserositis [1–3] and is the most common form of periodic inflammatory disease [4, 5]. As its name implies, FMF is more common in the Mediterranean region and affects mainly North African and Iraqi Jews, Arabs, Turks, and Armenians [3, 6, 7]. There are an estimated 100,000 people with FMF worldwide. The disease is caused by a mutation in the Mediterranean fever (MEFV) gene, located on chromosome 16, which encodes pyrin, a 781-amino acid protein [3]; M694V, V726A, and E148Q are the most commonly found mutations in various populations [8]. The diagnosis is based on clinical criteria [5, 7], although genetic analysis may assist in some cases.
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Cardiovascular abnormalities are rare in FMF. Endstage renal disease due to secondary AA amyloidosis was more common until the introduction of colchicine treatment, which significantly reduced the frequency and severity of attacks [4, 6]. In rare cases that amyloidosis does develop in FMF, it almost always spares the heart. Autonomic nervous system (ANS) dysfunction has been associated with several rheumatic diseases, such as lupus, rheumatoid arthritis, systemic sclerosis, Sjörgen syndrome, and polymyalgia rheumatica [9, 10]. Two recent studies reported a high rate of abnormal cardiovascular reactivity and occult dysautonomia in patients with FMF, on the basis of blood pressure, heart rate values, and cardiovascular reactivity score during a tilt test [11, 12]. By contrast, however, in a study of heart rate variability (HRV), considered a powerful and reliable marker of ANS function [13], our group found no difference between FMF patients without amyloidosis continuously treated with colchicine and normal control subjects [14]. To clarify this discrepancy, in the present study, we evaluated the response of patients with FMF to metronomic breathing, the Valsalva maneuver, and the Ewing maneuver [15–17], considered the most valuable tests for assessing ANS function [15]. An extensive review of the English medical literature revealed no similar studies.
Clin Rheumatol (2011) 30:1347–1351
Procedure
Methods
Participants were asked not to smoke, drink caffeinated beverages, or alcohol within 3 h prior to the procedure. Strenuous exercise 24 h prior to the procedure was avoided. Tests were conducted between 9:00 a.m. and 12:00 a.m., thus avoiding circadian influences on heart rate and ANS function. To prevent sympathetic overactivity, subjects were requested to empty their bladder before starting. Room temperature was maintained at 21–23°C. Participants were first instructed to lie motionless in a supine position for 10 min. ECG electrodes were placed on the limbs, according to standard procedure, and recordings were made with a standard device at a sampling rate of 2,000 Hz. To test the response to metronomic breathing, subjects were asked to remain in the supine position for 1 min and to perform forced breathing six times. After the heart rate returned to baseline, the Valsalva maneuver test was performed. Subjects were requested to take a deep breath and then slowly but forcefully exhale for 15–20 s to produce persistent positive intrathoracic pressure [15]. Thereafter, to test the response to the Ewing maneuver (active standing) [13], subjects were told to lie motionless for a few minutes, until the heart rate returned to normal, and then to quickly revert to an upright position and remain standing for 2 min. The data were saved in binary format and processed with custom-made computer software validated and tested for reproducibility according to accepted standards. The heart rate values were extracted on the basis of the intervals between the R spikes.
Subjects
Parameters evaluated
The study group included 33 patients with FMF, diagnosed according to the Tel Hashomer criteria [7]. An additional four patients were excluded because of the presence of other chronic clinical conditions (Behcet disease, hypothyroidism, Parkinson’s disease) and/or regular use of drugs known to affect the electrocardiogram (ECG), heart rate, or the sympathovagal balance. All FMF patients were treated with a preventative dose of colchicines (1–2.5 mg/day) using accepted protocols. None had had renal amyloidosis according to repeated normal urine analysis. Additionally, all FMF patients were attack-free, at least for a week prior to enrollment. Thirty-nine healthy, age- and sex-matched individuals served as the control group. None of the patients were smokers or had any known pulmonary disorder.
To evaluate the response to metronomic breathing, maximal heart rate (MaxHR) was measured during expirium (E) and minimal HR (MinHR) during inspirium (I). The difference ΔE/I was computed using the MaxHR–MinHR equation. Values above 10 bpm are considered normal [15]. The E/I ratio was calculated by dividing the longest mean RR interval during expirium by the shortest RR interval during inspirium [18]. E/I ratio above 1.23 is considered normal in young individuals [15]. Time domain analysis has been reported useful to quantify the mean response to a stimulus [15]. Power spectral analysis of HRV during metronomic breathing was performed with the fast Fourier transform algorithm for very low (0.003–0.04 Hz), low (0.04–0.15 Hz) and high (0.15–0.4 Hz) frequency bands. At rest, lowfrequency changes are mediated by both sympathetic and parasympathetic activity at rest; high-frequency changes are linked to the respiratory influence on heart rate and reflect parasympathetic activity [19–22]. The square root of the mean squared difference of successive RR intervals (RMSSD) was calculated as an indicator of the short-term component of rate variability [22].
Study design A comparative case–control design was used. The research protocol was approved by the institutional review board. All participants gave written informed consent.
Clin Rheumatol (2011) 30:1347–1351
When conducted properly, the Valsalva maneuver induces a complex four-phased response. Phase 1 is characterized by a decrease in heart rate and increase in blood pressure due to transient aortic compression. At the beginning of phase 2, blood pressure decreases, leading to activation of the baroreceptors and sympathetic activity, accompanied by an increase in heart rate and blood pressure and vasoconstriction. Phase 3 occurs shortly after the end of expiration and is characterized by a decrease in blood pressure and an increase in heart rate. In phase 4, blood pressure rises, leading to increased, baroreflexor-induced bradycardia [15]. The Valsalva ratio reflects the baroreflexmediated bradycardia and parasympathetic autonomic function and is calculated by dividing the highest heart rate during phase 2 and the lowest heart rate during phase 4. A ratio below 1.1 is considered abnormal [15]. The tachycardia ratio is calculated by dividing the shortest RR interval during the strain, which appears in phase 2, with the mean RR interval before the strain (computed from the 10-min ECG performed prior to onset of the tests) [23]. The bradycardia ratio is calculated by dividing the longest RR interval shortly after the strain (phase 4) by the mean RR interval before the strain [23]. In the Ewing maneuver, the sudden active standing causes a decrease in blood pressure and elevation in heart rate after approximately 15 s. After 30 s, blood pressure and heart rate usually normalize. The ratio between the highest RR interval length after 30 s and the lowest RR interval length after 15 s is referred to as the 30:15 ratio and reflects
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the orthostatic cardiac response. Values above 1.04 are usually considered normal [15]. Statistical analysis The statistical analysis was conducted by a blinded coinvestigator. Data were analyzed with Microsoft Excel version 2003 (Microsoft Corp., Seattle, WA) and JMP version 7.0 (SAS Institute, Cary, NC, USA). Results are presented as mean and standard deviations. Values more than two standard deviations from the normal range were defined as abnormal. Findings were compared between the groups by the Student t test. Statistical significance was set at a p value of less than 0.05.
Results The mean age of the FMF patient group was 35.3± 16.9 years, and of the control group, 34±13.9 years (p= 0.73). All FMF patients successfully completed the deep breathing test. The Valsalva maneuver test is more complex and requires significant cooperation. Sufficient positive expiratory pressure was achieved during the test in 20 FMF patients and 19 control subjects. The Ewing maneuver test was successfully completed by 30 FMF patients; in the other 3, the ECG was of insufficient quality and was excluded from the analysis.
Table 1 Comparison of autonomic test results between uncomplicated FMF patients and controls Test
Parameter
Metronomic breathing test
Minimal inspiratory HR (bpm) Maximal expiratory HR (bpm) ΔE/I (bpm) E/I ratio RMSSD (ms) VLF (ms2) LF (ms2) HF (ms2) Total power (ms2) Minimal RR phase 2 (ms)
Valsalva maneuver
Ewing maneuver
Maximal RR phase 4 (ms) Valsalva ratio Tachycardia ratio Bradycardia ratio Minimal RR after 15 s standing (ms) Maximal RR after 30 s standing (ms) 30:15 ratio
FMF
Control
P value
54.3±7.5 90.6±11.2 36.3±13.3 1.7±0.3 80.3±39.9 90.1±62.1 385.3±88.3 96.0±32.6 579.2±53.1 788.8±104.3
57.3±9.0 94.3±12.3 37±12.7 1.7±0.3 77.6±47.8 97±81.7 404.7±95.8 96.4±49.7 606.9±78.1 766.0±106.9
NS NS NS NS NS NS NS NS NS NS
1,059.2±150.6 1.35±0.17 0.85±0.11 1.11±0.12 607.7±82.5 879.0±153.1 1.45±0.20
1,004.1±138.7 1.32±0.16 0.85±0.12 1.14±0.17 589.5±90.4 878.7±120.1 1.50±0.22
NS NS NS NS NS NS NS
HR heart rate, E/I longest mean RR interval in expirium/shortest RR interval in inspirium, RMSSD square root of mean squared difference of successive RR intervals, VLF very low frequency, LF low frequency, HF high frequency, 30:15 ratio highest RR interval after 30 s/lowest RR interval after 15 s, NS nonsignificant (p
