Deteriorated Systolic Blood Pressure Recovery and Heart Rate Recovery After Graded Exercise in Children With Familial Mediterranean Fever.
The exercise stress test has been used to assess the cardiovascular performance of patients. Besides exercise capacity and chronotropic response, heart rate recovery (HRR) index and systolic blood pressure recovery (SBPR) rate can be calculated by the exercise stress test. (3,4) A normal HRR response occurs as a result of a balance between sympathetic and parasympathetic systems. The presence of abnormal HRR has been shown to be an independent marker of mortality. Increased sympathetic activity and delayed HRR response due to insufficient vagal reactivation have been shown as autonomic dysfunction findings in FMF patients. (5,6) SBPR can be obtained by determining the ratio of the third-minute systolic blood pressure of the recovery period to peak exercise systolic blood pressure, or the first-minute systolic blood pressure. It represents the reduction in systolic blood pressure after exercise. (7,8) A delay in the reduction of systolic blood pressure after exercise is an abnormal response and has been associated with increased cardiovascular risk. (9) There have been studies in the literature demonstrating abnormal HRR findings in FMF patients. To the best of our knowledge, no study has been conducted on individuals with FMF using SBPR, which is known to be associated with increased cardiovascular risk. Therefore, in this study, we aimed to investigate if cardiac involvement may occur in children with FMF without cardiovascular symptoms by using HRR and SBPR parameters.
PATIENTS AND METHODS
This study was conducted by the Pamukkale University's Medical Faculty Pediatric Rheumatology Department and Cardiology Department between January 2015 and June 2015. A total of 50 patients (26 males, 24 females; mean age 151[+ or -]33.4 month; range 60 to 216 month) who were not in attack period and were being followed-up with a FMF diagnosis according to Tel Hashomer and a new set of criteria for children (10,11) were included. In addition, 30 healthy controls (18 males, 12 females; mean age 143[+ or -]43.9 month; range 84 to 228 month) with no cardiologic or rheumatologic problems were included. Those with comorbid secondary chronic rheumatic problems to a FMF diagnosis were excluded. The onset age of disease, disease duration, clinical findings (fever, abdominal pain, chest pain, joint pain, and rash), dose and duration of medication, and Mediterranean fever mutation were recorded for each patient. All patients were evaluated by echocardiography before the study to eliminate congenital heart defects. The study protocol was approved by the Pamukkale University's Medical Faculty Ethics Committee. The study was conducted in accordance with the principles of the Declaration of Helsinki.
The patients and control group underwent a maximal graded exercise stress test using a Quinton treadmill system with the modified Bruce technique developed for children.  The 12-lead electrocardiographic monitorization was performed continuously during the test. Blood pressure and heart rate were measured automatically using a Tango exercise blood pressure-monitoring device before every stage and at the second minute in every stage of the exercise stress test. Maximal target heart rate during the exercise stress test was calculated as subtraction of age (year) from 220. The exercise stress test was continued until reaching 95% of the maximal heart rate. The HRR differences within the first five minutes after exercise (HRR1, HRR2, HRR3, HRR4, and HRR5) were calculated by subtracting the heart rate at each minute from the maximal heart rate. The ratio of the third-minute systolic blood pressure (SBP) of recovery period to peak SBP was considered to be SBPR1. Additionally, the ratio of the third-minute SBP of recovery period to the first-minute SBP was considered to be SBPR2.8 When the exercise capacity reached peak exercise, it was calculated as the total metabolic equivalent units.
All data were evaluated using the SPSS version 16.0 software (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean [+ or -] standard deviation and categorical variables were expressed as percentages. The Chi-square test and unpaired t test were used for evaluating comparisons of categorical and continuous variables between the two groups. Correlations between HRR and SBPR parameters were calculated by the Pearson's correlation analysis. A p value of [less than or equal to]0.05 was considered statistically significant.
All of the children's growth-development and physical examinations were normal. The mean age, height, and weight of FMF and control groups were similar ([151[+ or -]33.4 month, 143[+ or -]43.9 month p=0.46], [151[+ or -]15.9 cm, 148[+ or -]17.5 cm p=0.46], and [44.5[+ or -]14.6 kg, 42.6[+ or -]15.2 kg p=0.5], respectively). The most common clinical symptoms observed in the FMF group were abdominal pain (86%) and fever (62%). The clinical findings of FMF are presented in Table 1. All patients underwent genetic analysis for the Mediterranean fever mutation. The M694V mutation was the most commonly obtained mutation (32%). Comparison of the exercise stress test parameters of FMF and control groups is summarized in Table 2. Although all HRR parameters obtained were lower in the FMF group compared to the control group, there was a significant decrease in the HRR1 value (p=0.03). In addition, the SBPR1 and SPBR2 values obtained were higher in the FMF group compared to the control group (0.96[+ or -]0.12 vs. 0.88[+ or -]0.12 and 0.95[+ or -]0.09 vs. 0.91[+ or -]0.11, respectively); and the high SBPR1 value was statistically significant (p=0.02). Other exercise stress test parameters were similar between both groups.
The FMF clinical findings and correlation analysis results among the exercise stress test parameters are summarized in Table 3. The FMF presence had a negative correlation with HRR1 (r= -0.26, p=0.03), but a positive correlation with SBPR1 (r=0.29, p = 0.02). Moreover, there was a negative correlation of the M694V homozygous mutation with the HRR1 and the HRR2 values (r= -0.43, p=0.004; and r= -0.42, p=0.005). There was no correlation of the HRR and the SBPR values with age and daily dose of colchicine.
In this study, we detected deteriorated exercise stress test parameters in children with FMF.
Firstly, the HRR1 value was decreased in children with FMF compared to the control group. Secondly, the SBPR1 value was significantly increased in children with FMF. Thirdly, a negative correlation was found between FMF presence and HRR1, but a positive correlation was found between SBPR1 and FMF presence. Lastly, the presence of an M694V homozygous mutation was negatively correlated between HRR1 and HRR2 values.
The autonomic nervous system plays a major role in the regulation of cardiovascular functions. Studies in the literature have investigated the relationship between autoinflammatory diseases and cardiac autonomic dysfunction. 913,14) HRR is a frequently used technique for assessing cardiac autonomic dysfunction. (15) Deterioration was found in the HRR indexes of adult patients with FMF compared to healthy individuals in recent studies that Ardic (5) and Canpolat et al. (6) conducted. Contrary to these studies, Sahin et al. (16) found no difference between groups in terms of HRR parameters in their study conducted on children patients. In our study, deterioration was found in the HRR1 value for children with FMF compared to the healthy control group. These controversial results between Sahin et al. (16) and our study may arise from the different clinical and genotypical characteristics of the patient populations. While M694V mutation prevalence was 17% in their study, it was 32% in our study group. Also, the mean age of our patients was higher than in Sahin's study group.
Cardiovascular complications contribute to the morbidity and mortality rates in rheumatologic and autoinflammatory diseases. An insufficient reduction in heart rate after exercise has been shown to be a marker of autonomic dysfunction. (17) In addition, it has been documented as an independent indicator of all mortalities caused by cardiovascular and other diseases. (18,19) This autonomic dysfunction, characterized by insufficient vagal reactivation besides excessive sympathetic activation, has been associated with FMF. (20,21) Moreover, deteriorated HRR at the first minute after exercise is a powerful marker of mortality, independent from the increased workload of the heart during exercise, and myocardial perfusion defects. (22)
Changes in SBPR have been proposed to be associated with sympathetic and parasympathetic activity, systemic vascular resistance, and baroreflex sensitivity. A decreased SBP ratio after exercise has been considered to be a reflection of the physical activity and general health of an individual. A greater decrease in SBP in the recovery period after peak exercise reflects that the individual's physical activity and aerobic capacity are good. This response occurs as a result of a reduction in systemic vascular resistance because exercise improves vascular endothelial function and vasodilator capability. (23-27)
In several recent studies, markers indicating endothelial damage, such as thrombomodulin, adrenomedullin, and nitrite, have been found to be high in FMF patients in the non-attack period as well. (28,29) This finding proposes that ongoing subclinical inflammation and endothelial dysfunction are present also in the non-attack period in patients, and this is associated with increased cardiovascular problems. (30) We think that endothelial and autonomic dysfunction, together with subclinical inflammation, are responsible for a significantly higher SBPR1 value in FMF patients compared to the control group.
Although insufficient HRR and autonomic dysfunction are well known, there has been limited information demonstrating the relationship between SBPR and the autonomic nervous system.  Therefore, the demonstration of an insufficient SBPR1 response for the first time in FMF patients might be significant for indicating autonomic and endothelial dysfunction, which has been shown to be associated with FMF pathophysiology.
Considering the correlation analysis of clinical findings and the exercise stress test parameters of FMF patients, the presence of disease had a negative correlation with HRR1, and a positive correlation with SBPR1 also supported this finding. In addition, the negative correlation between HRR1 and HRR2 values in M694V mutation-positive patients was considered to be responsible for disease coursing with severe clinical symptoms. (32,33) This suggests that M694V homozygote patients have an increased cardiovascular risk.
The exercise capacities of the patient and control groups were good. No significant difference was found in terms of exercise capacity, initial heart rate, and peak heart rate. Therefore, we suggest that insufficiency in HRR and SBPR developed due to autonomic and endothelial dysfunction.
One of the limitations of this study was the limited number of patients. In addition, we do not know the exact effect of FMF SBPR. Therefore, further studies are necessary to identify SBPR correctly after exercise stress tests in patients with FMF.
In conclusion, to our knowledge, this is the first study indicating SBPR impairment and its relationship to the HRR of patients with FMF. Cardiac involvement may occur in FMF patients without cardiovascular symptoms. FMF is associated with insufficient SBPR and delayed HRR after exercise. In our opinion, insufficient SBPR and decreased HRR response may indicate increased cardiovascular risk in these patients despite normal exercise stress tests. Further studies are necessary to demonstrate the clinical findings of deteriorated autonomic and endothelial dysfunction in FMF patients, and to explain the exact underlying pathophysiological mechanisms in autoinflammatory diseases.
Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.
The authors received no financial support for the research and/or authorship of this article.
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Havva EVRENGUL,  Selcuk YUKSEL,  Mustafa DO?AN,  Dolunay GURSES,  Harun EVRENGUL 
 Department of Pediatric Nephrology, Medical Faculty of Pamukkale University, Denizli, Turkey
 Department of Pediatric Rheumatology, Medical Faculty of Pamukkale University, Denizli, Turkey
 Department of Pediatric Cardiology, Medical Faculty of Pamukkale University, Denizli, Turkey
 Department of Cardiology, Medical Faculty of Pamukkale University, Denizli, Turkey
Received: May 16, 2016 Accepted: October 28, 2016 Published online: April 05, 2017
Correspondence: Havva Evrengul, MD. Pamukkale Universitesi Tip Fakultesi Cocuk Nefrolojisi Bilim Dali, 20070 Kinikli, Denizli, Turkey. Tel: +90 505-484 00 97 e-mail: firstname.lastname@example.org
Table 1. Demographic and clinical features of patients with familial Mediterranean fever n % Mean [+ or -] SD Age (month) 151 [+ or -] 33.4 Height (centimeter) 151.4 [+ or -] 15.9 Weight (kg) 44.5 [+ or -] 14.6 Age at diagnosis (month) 100 [+ or -] 39 Disease duration (month 49.9 [+ or -] 26.8 Dose of colchicine (mg/day) 1.1 [+ or -] 0.21 Clinical manifestation Fever 31 62 Abdominal pain 43 86 Chest pain 1 2 Rash 1 2 Arthritis/arthralgia 16 32 Mutation Homozygous 20 40 Heterozygous 11 22 Compound heterozygous 17 34 No mutation 2 4 SD: Standard deviation. Table 2. Comparison of exercise stress test characteristics between patient and control groups FMF patients Controls Mean [+ or -] SD Mean [+ or -] SD Exercise capacity 11 [+ or -] 1.5 11.1 [+ or -] 1.3 (METs) Preexercise SBP (mmHg) 118 [+ or -] 14.6 117 [+ or -] 18 Preexercise DBP (mmHg) 75 [+ or -] 13 73 [+ or -] 13 Peak exercise HR, 172 [+ or -] 17 173 [+ or -] 17 beats/min Peak SBP (mmHg) 132 [+ or -] 21 137 [+ or -] 18 Peak DBP (mmHg) 74 [+ or -] 14 68 [+ or -] 16 Recovery SBP 1st min 133 [+ or -] 21 132 [+ or -] 19 (mmHg) Recovery SBP 3rd min 125 [+ or -] 15 119 [+ or -] 15 (mmHg) SBPR1 0.96 [+ or -] 0.12 0.88 [+ or -] 0.12 SBPR2 0.95 [+ or -] 0.09 0.91 [+ or -] 0.11 HRR 1st min, beats/min 48 [+ or -] 14 57 [+ or -] 20 HRR 2nd min, beats/min 63 [+ or -] 13 71 [+ or -] 20 HRR 3rd min, beats/min 65 [+ or -] 13 71 [+ or -] 17 HRR 4th min, beats/min 67 [+ or -] 11 72 [+ or -] 17 HRR 5th min, beats/min 69 [+ or -] 12 71 [+ or -] 13 p Exercise capacity 0.745 (METs) Preexercise SBP (mmHg) 0.813 Preexercise DBP (mmHg) 0.711 Peak exercise HR, 0.804 beats/min Peak SBP (mmHg) 0.330 Peak DBP (mmHg) 0.213 Recovery SBP 1st min 0.893 (mmHg) Recovery SBP 3rd min 0.148 (mmHg) SBPR1 0.020 SBPR2 0.17 HRR 1st min, beats/min 0.035 HRR 2nd min, beats/min 0.077 HRR 3rd min, beats/min 0.110 HRR 4th min, beats/min 0.203 HRR 5th min, beats/min 0.531 FMF: Familial Mediterranean fever; SD: Standard deviation; METs: Metabolic equivalent units; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; HR: Heart rate; SBPR: Systolic blood pressure recovery; HRR: Heart rate recovery. Table 3. Correlation analysis between clinical characteristics of familial Mediterranean fever patients and exercise stress test characteristics Existence FMF Age Daily dose of colchicine r p r p r SBPR1 0.294 0.020 0.047 0.715 -0.144 SBPR2 0.176 0.172 0.105 0.417 0.147 HRR 1st min, -0.269 0.035 0.080 0.537 -0.074 beats/min HRR 2nd min, -0.227 0.077 0.098 0.447 0.058 beats/min HRR 3rd min, -0.205 0.110 0.163 0.206 0.101 beats/min HRR 4th min, -0.164 0.203 0.145 0.262 0.064 beats/min HRR 5th min, -0.081 0.531 0.134 0.299 0.131 beats/min Daily dose of M694V homozygous colchicine p r p SBPR1 0.416 0.248 0.090 SBPR2 0.405 0.116 0.428 HRR 1st min, 0.677 -0.430 0.004 beats/min HRR 2nd min, 0.744 -0.421 0.005 beats/min HRR 3rd min, 0.572 -0.068 0.645 beats/min HRR 4th min, 0.720 -0.158 0.285 beats/min HRR 5th min, 0.462 -0.014 0.927 beats/min FMF: Familial Mediterranean fever; SBPR: Systolic blood pressure recovery; HRR: Heart rate recovery; Correlation coefficients: r value.
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|Title Annotation:||ORIGINAL ARTICLE|
|Author:||Evrengul, Havva; Yuksel, Selcuk; Dogan, Mustafa; Gurses, Dolunay; Evrengul, Harun|
|Publication:||Turkish Journal of Rheumatology|
|Date:||Sep 1, 2017|
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