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Z�lal �LGER1 (Ass.Prof.), Figen G�LEN2 (Prof.),  Arif Ruhi �ZY�REK1(Prof.)
1, Department of Pediatric Cardiology, Ege University Hospital , Bornova-izmir, Turkey�2 Department of Pediatric Allergy, Ege University Hospital , Bornova-izmir, Turkey







Correspondence:
Dr. Z�lal �lger
Ege �niversitesi �ocuk Hastanesi, 
Pediatrik Kardiyoloji Bilim Dal1
35100, Bornova-0zmir
Email:  HYPERLINK "mailto:drzulger@hotmail.com" drzulger@hotmail.com
Phone: 0532-2043208, 0232-3901001










Abdominal aortic stiffness in childhood onset asthma: A case control study
ABSTRACT
Background: Asthma is a chronic inflammatory disease and  chronic inflammation accelerates atherosclerosis. Abdominal aortic stiffness parameters can be used to detect early development of atherosclerosis. In this study, we aimed to evaluate abdominal aortic stiffness parameters in childhood onset asthma compared with the control group.
Methods: In this cross-sectional  study, we evaluated 50 patients with childhood onset asthma and  57 healthy children as controls. Patients having the the diagnosis of asthma at least three years were included for the study; Children having hypertension, hyperlipedemia, diabetes, smoking contact history, systemic disease were excluded.  All children were noninvasively evaluated with transthoracic echocardiography and abdominal aorta diameters were measured.  Aortic distensibility (DIS), aortic strain (S), pressure strain elastic modulus (Ep), pressure strain normalized by diastolic pressure (Ep*)  were calculated using the measured data.  In evaluation of the data Student�s t-test, Chi-square test, Pearson�s correlation test  were used.
Results: The study group consisted of 50 children(24 female, 26 male)  with asthma. According to GINA Guidelines, 26 of the patients had mild intermittant asthma, 6 of them had mild persistent and 18 of them had intermediate persistent asthma. None of the patients had severe asthma. In 37 of the asthma patients SpIgE was positive and these patients were accepted as atopic asthma; 27 of the patients received immunothearpy). There was no difference between the groups in terms of age, gender and BMI. No differences were evident between the groups in systolic-diastolic blood pressure, heart rate, blood cholesterol levels and respiratory function test�s parameters. There was not any significant difference between asthma and control group in the measurements of abdominal aorta systolic diameter(Ds),  abdominal aorta diastolic diameter(Dd),  aortic distensibility(DIS),  aortic strain(S),  pressure strain elastic modulus(Ep), pressure strain normalized by diastolic pressure(Ep*).  There was not any significant correlation between aortic stiffness parameters and  high sensitive C-reactive protein(hs-CRP), blood total cholesterol, LDL-cholesterol and HDL-cholesterol levels.
Conclusion: We did not find any difference between asthma patients and control group in aortic stiffness parameters (DIS, S, Ep and Ep*) and there was no difference in these parameters when we compared mild asthma patients with moderate asthma patients; these results may be due to antiinflamatory effect of inhaled steroids. Further studies are needed to validate these results. 
Key words: Asthma, children, aortic stiffness, abdominal aorta, echocardiography

Introduction
Asthma is an important health problem in children. Substantial evidence demonstrated asthma is a chronic inflammatory condition with activation of large numbers of immune and inflammatory cells within the airways. Recent studies reported that systemic inflammation is related to disease progression in asthma(1). Some proinflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor a (TNFa), and C reactive protein (CRP) are elevated in patients with asthma(1-3). Asthma and atherosclerosis are both chronic inflammatory diseases. Inflammation plays an important role in the impairment of endothelial functions. If the inflammation is chronic, this leads to an acceleration of the atherosclerosis(4). Elevated arterial stiffness, a marker of subclinical atherosclerosis, is associated with myocardial infarction, heart failure, stroke, renal disease, and elevated total mortality (5). 
Mounting evidence revealed that the patients with asthma are at increased risks of hypertension, pulmonary embolism, coronary heart disease, heart failure, and all cause mortality (6-9). Reduction of arterial distensibility increases arterial characteristic impedance, pulse pressure and the pulsatile cardiac work load. Arterial stiffness is an important  mechanical property, because it is related to vascular impedance and  in turn to the afterload that is presented to the left ventricle. Stiffness of the abdominal aorta increases with age and its usefulness as a noninvasive method  of assessment has been demonstrated (10-15).
The changes of abdominal aortic stiffness in children with asthma have not been clearly determined.  The purpose of the present study is to evaluate abdominal aortic stiffness in childhood onset asthma. 

Methods
Study design and population
Our study was designed as a cross-sectional observational study. 50 asthma patients(24 girls, 26 boys), aged 8-17 years, followed by the pediatric allergy department of our hospital for at least three years were included in this study. Children having hypertension, hyperlipedemia, diabetes, smoking contact history, systemic disease were excluded. Asthma was diagnosed from a history of intermittent wheezing and the presence of reversible airway obstruction as defined by at least a 12% improvement in FEV1 following bronchodilator administration and therapeutic response to anti-asthma treatment. The clinical severity of the asthma was determined using the criteria (appropriate clinical and respiratory function tests) defined in the Global Initiative for Asthma Guidelines (GINA)(16). 26 patients had mild intermittant, 6 patients had mild persistent and 18 patients had moderate persistent asthma.  In all patients, allergen sensitivity was performed with specific IgE (sIgE) and skin prick test (SPT) to aeroallergens.
SIgE levels: Serum allergen sIgE measurements were performed using CAP FEIA method  Pharmacia, Uppsala, Sweden), which is used to detect the sensitization in the serum against inhaled allergens (house dust mite, yeasts, animal dander, grass pollen, trees and wild grass); the result was considered positive if the measured value was greater than 0.35 kU/L.
Skin prick test (SPT): Commercial allergen solutions manufactured by Allergopharma (Joachim Ganzer KG, Reinbeck, Germany) were used for the skin test. A total of 44 different allergens consisting of housedust mite, grass, wild grass, tree pollens, fungi, animal dander, and insects were tested and children with at least one positive test were considered atopic.
Patients with clinical signs of asthma who had a positive sIgE, in addition to sensitivity against at least one aeroallargen on the SPT, were included in the atopic asthma groups. Immunocompromised patients, patients with a history of chronic  inflammation/rheumatological disorder, diabetes, hypertension, hipercholesterolemia and patients with autoimmune diseases, history of smoking exposure were excluded. Asthma patients having any symptom of lower or upper respiratory tract infection or asthma exacerbation within the previous 4 weeks were excluded. The control group consisted of 57 age and gender matched healthy children (8 to 17 years). Healthy children were chosen from those referred to a pediatric cardiology outpatient clinic due to innocent murmur. Control patients were evaluated with regard to chronic and/or severe infections, rheumatological and autoimmune disorders, and familial and personal history of atopy and hyperlipedemia. Children were included in the control group if they had no personal and familial history of atopy and no signs of atopic disorder.  As it is known to have an effect on oxidative status, the patients came from nonsmoking households, and the control group was also selected from non-smoking households. All the patients and control group in the study were weighed and body mass index(BMI) was calculated. All subjects in the study and control groups were evaluated with respiratory function test.
Local ethics committee approved the study. Informed consent was obtained from the parents of the all patients and control groups.


Baseline evaluation
Detailed medical history was obtained and physical examination was performed by the same pediatric cardiologist. The body height and weight were measured and the blood pressure was also recorded in all subjects. Weight was measured with an electronic digital scale that was sensitive to 0.1 kg. Body mass index (BMI) was calculated as weight (kg)/height (m2). Plasma lipid levels were measured after 12 hours of fasting. Serum total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels were measured with Alcyon 300 (Abbott Laboratories, USA) equipment by enzymatic method. High sensitive CRP (hs-CRP) level of study and control group were measured with automated analyzer based on turbidimetry method. 
Blood pressure measurements were done after 15 minutes of rest; Right brachial artery pressure was measured by sphygmomanometer with appropriate cuff. Both systolic (Ps) and diastolic blood pressure (Pd) were measured and after three measurements the mean value was obtained. Pulse pressure (PP) was calculated as PP=Ps-Pd.
Echocardiographic evaluation
All the patients and control group underwent 2D, M-Mode, and Doppler study using GE Vingmed Vivid 7- model echocardiography (GE Vingmed, Ultrasound AS, Horten, Norway) with 3MHz transducer. All the subjects were at rest and lying in the left decubitus position during the examination. Endiastolic left ventricle posterior wall thickness(LVPWTed), left ventricle end diastolic and systolic diameters (LVED, LVES), left atrial diameter (LA) and aortic anulus diameters were measured. The fractional shortening (FS) and the ejection fraction (EF) were obtained from  M-mode echocardiographic tracings with 2-D imaging. Measurements were determined with standard techniques in accordance with the recommendations of the American Society of Echocardiography(17). Mean pulmonary artery pressure of all subjects were calculated from pulmonary arter accelaration time.
A long axis view of abdominal aorta of the subxiphoid area was recorded and maximum systolic (Ds) and minimum diastolic diameter (Dd) was measured by M-mode echocardiography. All echocardiographic measurements were done by the same experienced pediatric cardiologist and  Intraobzerver variability was evaluated with Intraclass correlation coefficient (ICC); ICC  was 0.9 (excellent reliability).


Calculations
All aortic measurements were made as previously described by Lacombe et al. (10). Aortic strain (S) was calculated from the changes in aortic diameters and pressure strain elastic module was also calculated from the aortic strain and the changes in brachial artery systolic and diastolic pressure using the formulas: S=(Ds-Dd)/Dd, Ep=(Ps-Pd)/S. Pressure strain normalized (Ep*) by diastolic pressure was calculated by the equation: Ep*=Ep/Pd. Aortic distensibility (DIS) was calculated according to the previously proposed and evaluated equations(10-15) as;DIS=[2(Ds-Dd)/Dd(Ps-Pd)]x10-6cm dyne-1
S and DIS represent the distensibility or elasticity of the aortic wall; Ep, Ep* represent the stiffness of the aortic wall. Ep and Ep* are the mean stiffness of aorta.  S and Ep* are dimensionless ratios, whereas Ep has the dimension and is represented with the unit of N/m-2 (force/unit area). 

Statistical analysis
All statistical analyses were performed using Systat statistical software (version 15.0 for Windows; SPSS Inc, Chicago, IL, USA). Data were tested for homogeneity of variance with Shapiro-Wilk test. The Student�s t-test (unpaired) and Chi-square test were used for comparison of statistical difference between the groups. Correlations with the aortic elasticity parameters were evaluated with Pearson�s correlation test. Statistical significance was taken at p<0.05. All data were presented as the mean�SD.
Results
The study group consisted of 50 children(24 female, 26 male)  with asthma. According to GINA Guidlines, 26 of the patients had mild intermittant asthma, 6 of them had mild persistent and 18 of them had intermediate persistent asthma. None of the patients had severe asthma. In 37 of the asthma patients SpIgE was positive and these patients were accepted as atopic asthma; 27 of the patients received immunothearpy.  The mean age of the asthma group was 11,7�2.7 years, and of the control group12.3�2,8 years( 34 female, 23 male) . There was no difference between the groups in terms of age, gender and BMI (Table 1). No differences were evident between the groups in systolic-diastolic blood pressure, heart rate, blood cholesterol levels and respiratory function test�s parameters(Table 1).  


Table-I: Characteristics of asthma patients and control group
Asthma Patients (N=50)Control Group(N=57)Statististical significanceGender, Female/Male24/2634/23p>0,05Age, years11,7�2.712.3�2,8p>0,05Presence of atopy,  %37(74%)0 (0%)Immunotherapy 27(54%)0(0%)Duration of diagnosis of asthma, years8,1�2,8 (3-15)Weight, kg43,0�15,547,8�17,0p>0,05Height, cm148,0�15,9150,4�16,1p>0,05BMI, kg/m�19,0�4,120,5�4,3p>0,05Systolic Blood Pressure, mmHg101,1�10,4102,4�10,4p>0,05Diastolic Blood Pressure, mmHg63,5�9,964,9�9,8p>0,05Mean Blood Pressure, mmHg76,0�9,277,4�9,3p>0,05Heart Rate, beat/min84�1585�14p>0,05Total cholesterol, mg/dl152,5�32,6147,5�24,6p>0,05LDL cholesterol, mg/dl83,6�17,879,6�18,1p>0,05HDL cholesterol, mg/dl55,6�17,350,7�11,5p>0,05Hs-CRP, mg/dl2,12�0,410,79�0,20p<0,05FVC,  % predicted87,3�13,687,1�10,6p>0,05FEV1,  % predicted97,7�14,999,2�11,1p>0,05FEV1/FVC,  %95,2�5,897,0�4,3p>0,05PEF, % predicted92,8�16,689,8�14,6p>0,05Data are presented as mean�standard deviation
BMI-Body mass index, FEV1-Forced expiratory volume in 1 second, FVC-Forced vital capacity, HDL-High density lipoprotein, LDL-low density lipoprotein, PEF-Peak expiratory flow


Asthma patients and control group were evaluated with transthorasic echocardiography; There was no significant difference between two groups in the measurements of end diastolic left ventricule posterior wall thickness (LVPWTed), Left ventricule enddiastolic and ens sistolic diameters (LVED, LVES), end diastolic interventricular septum thickness,(IVSed), left  atrium diameter (LA), aortic anulus diameter, ejection fraction (EF) and fractional shortening (FS)(Table II). Mean pulmonary pressure (mPAP) of asthma group was higher than the control group (19.9 �7.1 vs 12.6�6.2mmHg)and this difference was statistically significant (p<0,05). There was not any correlation between mPAP and aortic stiffness parameters(pearson correlation analysis). In 15 of asthma patients echocardiography revealed mild tricuspit regurgitation and right ventricule systolic pressure was calculated from regurgitant flow; Avarage right ventricle systolic pressure of these 15 patients was 27,2�5,7 mmHg. Since we evaluated the asthma patients without asthma exacerbation within the previous 4 weeks, There was no difference in baseline respiratory function test parameters between study and control groups. 


Table II: Echocardiographic findings of asthma and control groups
Asthma Patients (N=50)Control Group(N=57)Statististical significanceLVPWTed, mm7,1�0,17,0�0,1p>0,05LVED, mm40,1�4,640,4�4,8p>0,05LVES, mm25,8�4,524,7�3,9p>0,05IVSed, mm7,4�1,17,2�1,1p>0,05LA, mm25,3�4,023,2�3,7p>0,05Aortic anulus, mm16,8�3,217,1�2,6p>0,05EF, %72�1076�8p>0,05FS, %36�738�7p>0,05mPAP, mmHg19.9�7.112.6�6.2p<0,05Data are presented as mean�standard deviation
EF-Ejection fraction, FS- fractional shortening, LA- Left atrial diameter , LVED-Left ventricular end diastolic diameter, LVES-left ventricle systolic diameter, LVPWTed-Endiastolic left ventricle posterior  wall thickness(LVPWTed) , mPAP-mean pulmonary artery pressure
There was not any significant difference between asthma and control group in the measurements of abdominal aorta systolic diameter(Ds), abdominal aorta diastolic diameter(Dd), aortic distensibility(DIS),  aortic strain(S),  pressure strain elastic modulus(Ep), pressure strain normalized by diastolic pressure(Ep*) (Table III). There was not any significant correlation between aortic stiffness parameters and  blood total cholesterol, LDL-cholesterol and HDL-cholesterol levels(Pearson correlation analysis). 

Table III: Aortic stiffness parameters in asthma and control groups
Asthma Patients (N=50)Control Group(N=57)Statististical significancePeak aortic velocity, cm/sec125,6�16,7123,5�17,9p>0,05Ds, mm11,4�2,011,1�1,9p>0,05Dd, mm8,2�1,58,2�1,8p>0,05DIS, 10-6 cm2 dyne-11,35�0,521,41�0,66p>0,05S0,38�0,110,37�0,14p>0,05Ep, N/m-2107,5�39,0116,5�55,9p>0,05Ep*1,75�0,731,83�0,90p>0,05Data are presented as mean�standard deviation
Dd - abdominal aorta diastolic diameter, DIS - aortic distensibility, Ds - abdominal aorta systolic diameter, Ep - pressure strain elastic modulus, Ep* - pressure strain normalized by diastolic pressure S � aortic strain 
Out of 50 asthma patients, 18 patients had intermediate severity asthma. Aortic stiffness paramaters compared between intermediate severity asthma patients and control group; There was not any statistically significant difference between the groups (Table IV). 

Table IV: Aortic stiffness parameters in intermediate severity asthma patients and control group
Intermediate severity Asthma Patients (N=18)Control Group(N=57)Statististical significancePeak aortic velocity, cm/sec125,6�16,7123,5�17,9p>0,05Ds, mm11,4�2,011,1�1,9p>0,05Dd, mm8,2�1,58,2�1,8p>0,05DIS, 10-6 cm2 dyne-11,31�0,511,41�0,66p>0,05S0,39�0,100,37�0,14p>0,05Ep, N/m-2105,9�42,4116,5�55,9p>0,05Ep*1,71�0,741,83�0,90p>0,05Data are presented as mean�standard deviation
Dd - abdominal aorta diastolic diameter, DIS - aortic distensibility, Ds - abdominal aorta systolic diameter, Ep - pressure strain elastic modulus, Ep* - pressure strain normalized by diastolic pressure, S � aortic strain, 
We evaluated the effects of presence of atopy and severity of asthma on aortic stiffness parameters; There was not any difference in aortic stiffness parameters between atopic asthma patients and control group(Table V).   

Table-V: Aortic stiffness parameters in asthma patients with atopy and control group
Asthma Patients with atopy  (N=37)Control Group(N=57)Statististical significancePeak aortic velocity, cm/sec128,0�16,5123,5�17,9p>0,05Ds, mm11,5�1,911,1�1,9p>0,05Dd, mm8,3�1,38,2�1,8p>0,05DIS, 10-6 cm2 dyne-11,31�0,511,41�0,66p>0,05S0,38�0,120,37�0,14p>0,05Ep, N/m-2105,4�35,6116,5�55,9p>0,05Ep*1,69�0,661,83�0,90p>0,05Data are presented as mean�standard deviation
Dd - abdominal aorta diastolic diameter, DIS - aortic distensibility, Ds - abdominal aorta systolic diameter, Ep - pressure strain elastic modulus, Ep* - pressure strain normalized by diastolic pressure , S � aortic strain
Discussion
The present cross-sectional study was undertaken to comparatively evaluate the elastic properties of abdominal aorta in children with asthma and control group. 
Measured aortic distensibility has been shown to be useful in adults as a noninvasive method in the early detection of atherosclerosis. Lacombe et al. demonstrated that in subjects older than 20 years of age S, Ep and Ep* are related to age due to atherosclerosis(10).We calculated S, Ep, Ep* and distensibility using the formula proposed by Lacombe and Lage et al.(10,15).  Okubo found that aortic distensibility varies with age: it is low in infants, improves gradually to peak during the ages 10�15 years, and decreases with age thereafter(11).
If there is atherosclerosis, aortic stiffness, pressure strain elastic modulus(Ep) and  pressure strain normalized by diastolic pressure(Ep*) increase. Whereas, aortic distensibility(DIS) and  aortic strain(S) decrease. 
Transthoracic echocardiography provides a highly accurate and reliable evaluation of regional aortic elastic properties. Stiffness and distensibility assessment of abdominal aorta has a very important role in the evaluation of the arterial system elasticity.
The increased stiffness causes an increase in pulse pressure pressure and a decrease in diastolic blood pressure, thereby causing increased left ventricular afterload and increased fatigue in arterial wall tissues. Srain and distensibility represent the elasticity of the abdominal aortic wall. Previous studies have shown thatmeasurement of aortic stiffness helps early detection of arteriosclerosis and the abdominal aorta becomes stiffer with age,hypertension, atherosclerosis, tobacco-smoking, obesity, �-thalassemia patients, and patients of Marfan syndrome and Kawasaki disease (11, 13, 14).
Asthma and atherosclerosis are both chronic inflammatory diseases. Inflammation plays an important role in the impairment of endothelial functions. If the inflammation is chronic, this leads to an acceleration of the atherosclerosis(18). Some studies have even stated that asthma itself could be a risk factor for stroke and heart disease(19,20). Asthma is a chronic inflammatory pulmonary disease related to increased oxidative stress(21). The association between chronic inflammation and oxidative stress is well documented. Elevated levels of reactive oxygen species, such as hydroxyl radicals, superoxides, and peroxides in inflammatory conditions have been reported previously(22).                         Chronic inflammation has also been increasingly associated with atherosclerosis endothelial dysfunction  and arterial stiffness (AS) and these in turn with adverse cardiovascular events and common inflammatory pathways(23,24).
There are some studies evaluating the relationship between adult onset asthma and atherosclerosis. But, the results are contradictory: Onufrak et al showed that  in adult onset asthma patients, the risk of atherosclerosis increased(25). 
However, in another study, carotid atherosclerosis was reduced in asthmatic adult patients treated with inhaled corticosteroids compared with matched controls and they found that inhaled corticosteroids had protective effects against atherosclerosis(26). 
Weiler et al found significant correlations between measurements of periferic arterial stiffness and FEV1 in adult asthmatics, and suggested the presence of a common systemic, most likely inflammatory pathway involving both the cardiovascular and respiratory systems(27). In another adult study, Sun et al found that the patients with severe asthma had increased  brachial ankle pulse wave velocity (baPWV ) and CRP compared with the patients with stable asthma and control subjects. Furthermore, baPWV was elevated in stable asthma compared with control subjects(28).
However, there are only a few studies evaluating the relationship between childhood onset asthma and atherosclerosis. In the study of cakmak et al, carotid intima media thickness (CIMT) of the asthmatic children was found higher compared to the control group and there was a positive correlation between CIMT and total oxidant status. They studied only children with mild asthma,not using prophylactic inhaled corticosteroids.  
In all these studies, CIMT was evaluated as a marker of atherosclerosis. However, in our study, we evaluated abdominal aortic stiffness as a sign of atherosclerosis in childhood asthma. 
Study limitations
In our study, study population consisted of children with stable asthma. We did not evaluate aortic stiffness parameters in children with severe asthma. Further studies including larger population size and the children with severe asthma may disclose  different results regarding abdominal aortic stiffness. In our study, as an inflammatory marker, we used only hs-CRP; Inflammatory marker showing oxidant status could not be studied. 
Conclusion
We evaluated the aortic stiffness parameters in childhood onset asthma; We evaluated children having the diagnosis of asthma for at least 3 years (avarage duration of diagnosis: 8,1�2,8 ). We did not find any difference between chidhood onset asthma patients and the control group in aortic stiffness parameters (DIS, S, Ep and Ep*). There was no difference in these parameters when we compared mild asthma patients with moderate asthma patients. These results may be due to antiinflammatory effect of inhaled corticosteroid treatment.
Since, there is not any study in the literature evaluating abdominal aortic stiffness in childhood onset asthma patients; We can not compare our results with other studies. Further studies are needed to validate these results. 
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