Abstract

Background: This study aims to investigate aortic stiffness, distensibility, and strain, which can be used to detect atherosclerosis in asthmatic children, and their impact on cardiac functions.

Methods: Between January 2012 and November 2014, a total of 21 pediatric patients (11 males, 10 females; mean age: 11.3±3.2 years; range, 6 to 15 years) with asthma and 17 healthy children (10 males, 7 females; mean age 12.8±3.8 years; range 7 to 16 years) were included. Using abdominal ultrasound, the stiffness, distensibility, and strain of the abdominal aorta were calculated. Echocardiographic examination was also performed on all children.

Results: Aortic stiffness was higher, while distensibility and strain values were lower in the asthmatic group, compared to the controls. Of the difference in the aortic strain, 30.3% was due to asthma, 22.5% to pulse pressure, 21.8% to mid-wall shortening fraction, and 17.2% to the left ventricular meridional wall stress. There was a very strong linear correlation between the left ventricular mass index and meridional wall stress (r=0.934), myocardial fiber stress (r=0.918), and predicted mid-wall fiber shortening for a measured fiber stress (r=0.918). Of the difference in the aortic distensibility, 40.6% was due to asthma, 18% to systolic blood pressure, and 12.2% to meridional end-systolic wall stress. Of the difference in the aortic stiffness, 24.7% was related to the diastolic blood pressure, 20.3% to ejection time, and 17.4% to the age variability.

Conclusion: According to our study results, aortic distensibility and strain decrease, while aortic stiffness increases in asthmatic children. Therefore, we suggest that asthmatic children should be followed closely for the development of atherosclerosis.

Asthma is a chronic inflammatory disorder of the airways which is associated with airway obstruction and hyperresponsiveness, and is characterized with recurrent episodes of wheezing, shortness of breath, and coughing.[1] Bronchial asthma affects several organs including the heart.[2] Atherosclerosis and asthma are both chronic inflammatory disorders. Asthma is not only associated with multiple markers of chronic systemic inflammation, but also with an increased risk of atherogenesis.[2] Chronic inflammation via common inflammatory pathways[3] is associated with atherosclerosis,[4] endothelial dysfunction,[5] and arterial stiffness[6] and adverse cardiovascular events, eventually.[7] In the literature, there are some studies investigating the relationship between the peripheral arterial stiffness and atherosclerosis and adverse cardiovascular outcomes.[8] Inflammation causes impairment of endothelial cell function and accelerates atherosclerosis.[5] Several studies reported that patients with asthma are faced with an increased risk of pulmonary embolism, hypertension, coronary heart disease, and heart failure.[3,7,8]

Elevated arterial stiffness is associated with myocardial infarction, heart failure, renal disease, stroke, and increased total mortality rates in adults.[9] Therefore, elevated arterial stiffness is considered to be a marker of subclinical atherosclerosis.[9] Arterial stiffness is a mechanical feature related to the vascular impedance and the afterload on the left ventricle (LV). Reduction in arterial distensibility leads to an increased pulse pressure and impedance of arterial flow, and pulsatile cardiac workload.[10]

In this study, we investigated aortic stiffness, distensibility, and strain, which can be used to detect atherosclerosis in asthmatic children, and its impact on cardiac functions.

Methods

This retrospective study included a total of 21 pediatric patients (11 boys, and 10 girls; mean age 11.3±3.2 years; range, 6 to 15 years) who were randomly selected from the patient population with bronchial asthma and 17 healthy subjects (10 boys and 7 girls; mean age 12.8±3.8 years; range 7 to 16) years). Bronchial asthma was defined according to the Global Initiative for Asthma (GINA) criteria.[1] Exclusion criteria were as follows: existing comorbidities, upper or lower respiratory infection, allergic rhinitis, gastroesophageal reflux, or obesity; chronic cardiovascular or pulmonary diseases; acute asthma attack, or use of oral or inhaled steroids within the past four weeks.

The control group was selected from healthy children.

The study protocol was approved by the Bozok University Medical Faculty Ethics Committee. The study was conducted in accordance with the principles of the Declaration of Helsinki.

All children included in the study underwent a full history-taking and complete physical examination performed by a single physician. The heart rate and blood pressure (BP) of all children were recorded which were performed after 15 minutes of rest. The right brachial artery pressure was measured by a sphygmomanometer with an appropriate cuff. Both systolic (Ps) and diastolic (Pd) blood pressures were measured, and the mean value was recorded following three consecutive measurements. Pulse pressure (PP) was also calculated as PP = Ps-Pd.

Blood samples were obtained from the patients after a 12-hour fasting and were measured for glucose, total cholesterol, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol.

Abdominal aorta artery was measured from the infrarenal segment, 2 cm distal to the renal arteries and at the widest arterial diameter at systole and the narrowest arterial diameter at diastole. The investigator performed and recorded three simultaneous arterial measurements in all children, using GE Logiq 7S Duplex ultrasonography (General Electric, Wauwatosa, WI, USA) with probe at a frequency of 3.1-10 MHz for B scan.

Aortic distensibility, strain, and stiffness were calculated as follows:

Distensibility (cm2. d yn-1)= 2 x (arterial d iameter systolic-arterial diameter-diastolic)/(arterial diameterdiastolic x pulse pressure).[10]

Strain= (systolic diameter-diastolic diameter)/ diastolic diameter).[10]

Stiffness (mmHg)= Logarithm (systolic BP/diastolic BP)/strain.[11]

An electrocardiogram was recorded for all patients. Transthoracic echocardiography was performed by a single experienced pediatric cardiologist who was blinded to the study groups. The following parameters were monitored echocardiographically: left ventricle end-diastolic pressure (LVEDP), left ventricle mass (LVM, g) according to the formula of Devereux,[12] peak early diastolic flow velocity (Peak E, cm/s) and peak late diastolic flow velocity (Peak A, cm/s), ratio between heights of early and late diastolic flow velocity peaks (E/A ratio) for mitral valve, deceleration time (DT, ms), LV meridional end-systolic wall stress (ESWSm, g/cm2), mid-wall shortening fraction (SFmid), heart rate corrected circumferential fiber shortening (VCFc), mid-wall VCFc, myocardial fiber stress (MFS, g/cm2), and meridional LV wall stress (WSM, dyn/cm2).

The following parameters were monitored by tissue Doppler echocardiography (TDE): annular peak velocity during late diastole (A’), annular peak velocity during early diastole (E’), isovolumetric relaxation time (IVRT), isovolumetric contraction time (IVCT), annular peak velocity during systole (S’), and ejection time (ET).

Mitral valve filling velocities were recorded from the apical four-chamber view with the pulse-wave Doppler during diastole. E, A, and DT were used as both ventricular diastolic function parameters. The ratios of E to A were calculated.

VCFc (circ/s)= (SF x (1500/heart rate)0.5 / LV ET)

Midwall VCFc w as c alculated a s= 0 .0007 x f iber stress + 0.65

ESWSm was calculated by the method of Grossman et al.[13] and MFS according to the formula recommended by Regen.[14]

SFmid= [(LVED+hd/2+sd/2)-LVES-mwst]/(LVED + hd/2 + sd/2)

The mwst was calculated as= [(LVED + (hd + sd)/2]3 - LVED3 + LVES3)0.333 –LVES]

sd= end-diastolic septal thickness, hd= left ventricular end-diastolic posterior wall thickness

Peak systolic (S’) and early and late diastolic velocities (E’ and A’) were measured from the apical four-chamber view with the pulsed-wave Doppler sample volume at the mitral annulus.

Cardiac time intervals, including IVCT from the end of mitral flow to the beginning of aortic flow, IVRT from the end of aortic flow to the beginning of mitral flow, and ET from the beginning to the end of the mitral flow were also measured.

Statistical analysis
Statistical analysis was performed using SPSS version 16.0 software (SPSS Inc., Chicago, IL, USA). The Student’s t-test, correlation analysis, regression, analysis, and the analysis of covariance (ANCOVA) were used to analyze data. The comparison of the arithmetic means of the radiographic results of aortic distensibility, strain, and stiffness between children with or without asthma was performed using independent t-test. The correlation between cardiac parameters and the dependent variables of aortic distensibility, strain, and stiffness were examined separately in patients and control subjects. The cardiac variables which were found to be significant in the correlation analysis were included into the ANCOVA as covariates to examine the differences in aortic distensibility, strain, and stiffness between the patient and control groups (fixed factor). In case of a highly significant correlation (r≥0.80) between the cardiac parameters, the variable with the highest degree of correlation with the aorta was included in the ANCOVA. Since the cardiac parameters can be affected by age, the age variable was also included in multiple ANCOVA as a covariate. Further tests were performed to determine whether these differences were due to asthma or other cardiac parameters. Prior to ANCOVA, the homogeneity of the group variances was assessed using the Levene’s test and the test was performed, when homogeneity was ascertained. A p value of <0.05 was considered statistically significant.

Results

There was no significant difference in age, systolic BP, pulse pressure, heart rate, fasting glucose, and HDL and LDL cholesterol levels between the groups (Table 1).

Table 1: Demographic and clinical characteristics of asthmatic children and healthy controls

On the other hand, the aortic strain and distensibility were lower, while stiffness was higher in asthmatic children compared to the controls (Table 2).

Table 2: Radiographic measurements of aorta in asthmatic children and healthy controls

There was also a significant correlation between the cardiac parameters and aortic distensibility, strain, and stiffness (Table 3). Aortic distensibility was positively correlated with S/E’ and SFmid in the asthmatic group and positively correlated with systolic BP, pulse pressure, VCFc, SFmid and negatively correlated with IVCT, ET, ESWSm and age in the control group. Aortic strain was also positively correlated with SFmid in asthmatic children and positively correlated with LVM, WSM, MFSm, and mid-wall VCFc and negatively correlated with pulse pressure and ESWSm in the control group. Aortic stiffness was positively correlated with pulse pressure and ET and negatively correlated with diastolic BPd in the asthmatic group and positively correlated with ESWSm and negatively correlated with diastolic BP in the control group.

A total of 52.9% (R2=0.529) of the low distensibility in the aorta was specifically attributed to asthma, followed by systolic BP and ESWSm. Of this difference, 40.6% was due to asthma, 18% to systolic BP, and 12.2% to ESWSm (Table 4).

Table 3: Correlation between radiographic measurements of the aorta and cardiac parameters in asthmatic children and healthy controls

Table 4: Aortic distensibility by ANCOVA according to covariate variables

Of the low strain in aorta, 61% (R2=0.61) was specifically attributed to asthma, followed by pulse pressure, SFmid, and WSM. Of this difference, 30.3% was due to asthma, 22.5% to pulse pressure, 21.8% to SFmid, and 17.2% to WSM. There was a very strong linear correlation between LVM with WSM (r=0.934), MFS (r=0.918) and mid-wall VCFc (r=0.918); as a result, changes in these parameters also affected the aortic strain (Table 5).

Table 5: Aortic strain by ANCOVA according to covariate variables

A total of 68.7% (R2=0.687) of the increased stiffness in the aorta was mainly attributed to diastolic BP, followed by ET and age. Of these differences, 24.7% was related to the diastolic BP, 20.3% to ET, and 17.4% to age variability. There was no significant correlation between asthma (10.8%) and ESWSm (9.7%) (values were within the reference ranges) (Table 6).

Table 6: Aortic stiffness by ANCOVA according to covariate variables

Discussion

The present study investigated the elasticity properties of the abdominal aorta in children with asthma. On the basis of the association between chronic inflammation and atherosclerosis, we hypothesized that the impaired elasticity in children with asthma could possibly lead to an increased risk of atherosclerotic disease. Therefore, the abdominal aorta was assessed. During the atherosclerotic process, increased arterial stiffness and decreased arterial distensibility and strain have been previously reported.[15] Consistent with the previous findings, our results showed decreased distensibility and strain in the aorta with increased stiffness.

On the other hand, there is a scarcity of published data on the association between the childhood-onset asthma and atherosclerosis and only few studies evaluated elasticity in asthmatic children to date. Steinmann et al.[16] showed an increased arterial stiffness in children with asthma using carotid-femoral pulse wave velocity measurements. Weiler et al.[17] examined the arterial stiffness in peripheral large and small arteries and found no difference between the asthmatic adults and controls. These authors also reported a positive correlation between the small arterial elasticity index and forced expiratory volume at one second (FEV1). Brachial-ankle pulse wave velocity measurements were performed to assess the arterial stiffness in the study by Sun et al.,[18] where an increased arterial stiffness was found among the adult asthmatic patients with stable disease, compared to the healthy controls. In the aforementioned study, a negative correlation between the brachial-ankle pulse wave velocity and FEV1 w as f ound. O n t he o ther hand, in a recent study by Ülger et al.,[15] no difference between the asthmatic children and control subjects was found in terms of the aortic stiffness parameters. Inhaled steroids were reported as a possible reason for decreased aortic stiffness. Ayer et al.[19] suggested that the reduction in the lung volume during early childhood might be associated with increased arterial stiffness. However, Bhatt et al.[20] reported no significant difference between the systemic inflammation markers and arterial stiffness in patients with chronic obstructive pulmonary disease.

Decreased arterial distensibility is a risk factor for cardiovascular disease. Several studies have shown the utility of aortic distensibility as a non-invasive method in the detection of early atherosclerosis among adults.[21] It has been also demonstrated that arterial distensibility decreases in several diseases, such as polyarteritis nodosa,[21] systemic lupus erythematosus,[22] and hypertension.[23] Mikola et a l.[24] studied the aorta and carotid arteries in children and reported that aortic and carotid distensibility decreased with age, which was more pronounced in boys than in girls. Increased stiffness leads to decreased diastolic BP and increased pulse pressure, causing increased left ventricular afterload, and a wear-and-tear effect on the arterial wall tissue.[24]

Furthermore, ESWSm is an index of total forces per unit of myocardium.[25] It has been used as a measurement tool of myocardial afterload, the counter force limiting LV ejection.[25] Chamber geometry of the cardiac structure also has an effect on both ventricular contractility and myocardial performance and needs to be identified by measuring ESWSm and MFS. The ESWSm seems to be related to chamber shape and mass/volume ratio and displays the forces opposing predominantly meridional and circumferential planes. In the present study, we found that asthma disease, systolic BP, and ESWSm all had an effect on the aortic distensibility. We also observed a positive correlation between the aortic distensibility and systolic BP, and a negative correlation between the aortic distensibility and ESWSm.

This study also showed that asthma disease, WSM, pulse pressure, LVM, SFmid, MFS and mid-wall VCFc affected the aortic strain. There was a positive correlation between LVM and SFmid and aortic strain and a negative correlation between WSM, MFS and mid-wall VCFc and aortic strain. We also observed decreased aortic distensibility and increased stiffness in the patients with asthma. On one hand, this leads to an increased LVM with an increased afterload. On the other hand, it increases the workload and stress on both meridional and circumferential fibers and also the myocardial stress. The ventricular contractility and myocardial performance may be affected by the chamber geometry, which should be identified by measuring ESWSm, mid-wall VCFc, and MFS. The latter, as the representative of myofiber afterload, is a more accurate index of the afterload for the hypertrophic or dilated LV.[26] As being systolic ejection index of deeper layers of myocardium, SFmid provides more physiologically appropriate measurements of LV in wall thickness and conditions such as LV concentric hypertrophy and provides information to assess the myocardial performance.[27]

Aortic stiffness was found to be related to the diastolic BP and ET. There was a negative relation with diastolic BP and a positive relation with ET and aortic stiffness. Increased stiffness caused prolonged ET with an increased afterload. There was no significant correlation between asthma and ESWSm (values were within reference ranges). In previous studies, ventricular mass and function have been shown to be associated with aortic stiffness.[28,29] To date, several studies have not shown a supporting finding for such a relationship.[29-31] However, in these studies, the systolic function of the heart was evaluated, but not the diastolic function. The most important factor in the development of cardiac hypertrophy is the end-systolic stress.[13] Endsystolic stress is influenced by ventricular geometry, as well as the aortic function.[27,28] To overcome the endsystolic stress, there are some structural changes in the myocardium, which may result in myocardial systolic and diastolic stiffness, eventually.[32]

In the present study, there was no correlation between the aortic elasticity parameters and ventricular diastolic functions, such as E/A, IVRT, IVCT, DT.

To the best of our knowledge, we were unable to find any study evaluating the correlation between the aortic distensibility, strain, and stiffness with cardiac parameters, such as SFmid, WSM, MFS, mid-wall VCFc, or ESWSm in asthmatic children. Therefore, we were unable to compare our results with previous studies in the pediatric age group. We, hence, recommend further large-scale studies to confirm these findings.

In conclusion, aortic distensibility and strain decrease and stiffness increases in asthmatic children. Therefore, these individuals should be followed closely for the development of atherosclerosis.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

References

1) Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) (2006) Available from: http://www.ginasthma.org/.

2) Wu TL, Chang PY, Tsao KC, Sun CF, Wu LL, Wu JT. A panel of multiple markers associated with chronic systemic inflammation and the risk of atherogenesis is detectable in asthma and chronic obstructive pulmonary disease. J Clin Lab Anal 2007;21:367-71.

3) Ramasamy R, Yan SF, Herold K, Clynes R, Schmidt AM. Receptor for advanced glycation end products: fundamental roles in the inflammatory response: winding the way to the pathogenesis of endothelial dysfunction and atherosclerosis. Ann N Y Acad Sci 2008;1126:7-13.

4) Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012;32:2045-51.

5) Zhang C. The role of inflammatory cytokines in endothelial dysfunction. Basic Res Cardiol 2008;103:398-406.

6) Mahmud A, Feely J. Arterial stiffness is related to systemic inflammation in essential hypertension. Hypertension 2005;46:1118-22.

7) Anderson TJ. Arterial stiffness or endothelial dysfunction as a surrogate marker of vascular risk. Can J Cardiol 2006;22:72-80.

8) Cohn JN. Arterial compliance to stratify cardiovascular risk: more precision in therapeutic decision making. Am J Hypertens 2001;14:258-263.

9) Safar ME, Blacher J, Jankowski P. Arterial stiffness, pulse pressure, and cardiovascular disease-is it possible to break the vicious circle? Atherosclerosis 2011;218:263-71.

10) Lacombe F, Dart A, Dewar E, Jennings G, Cameron J, Laufer E. Arterial elastic properties in man: a comparison of echo-Doppler indices of aortic stiffness. Eur Heart J 1992;13:1040-5.

11) Iannuzzi A, Licenziati MR, Acampora C, Salvatore V, De Marco D, Mayer MC, et al. Preclinical changes in the mechanical properties of abdominal aorta in obese children. Metabolism 2004;53:1243-6.

12) Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57:450-8.

13) Grossman W, Jones D, McLaurin LP. Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 1975;56:56-64.

14) Regen DM. Calculation of left ventricular wall stress. Circ Res 1990;67:245-52.

15) Ülger Z, Gülen F, Özyürek AR. Abdominal aortic stiffness as a marker of atherosclerosis in childhood-onset asthma: a case-control study. Cardiovasc J Afr 2015;26:8-12.

16) Steinmann M, Abbas C, Singer F, Casaulta C, Regamey N, Haffner D, et al. Arterial stiffness is increased in asthmatic children. Eur J Pediatr 2015;174:519-23.

17) Weiler Z, Zeldin Y, Magen E, Zamir D, Kidon MI. Pulmonary function correlates with arterial stiffness in asthmatic patients. Respir Med 2010;104:197-203.

18) Sun WX, Jin D, Li Y, Wang RT. Increased arterial stiffness in stable and severe asthma. Respir Med 2014;108:57-62.

19) Ayer JG, Belousova EG, Harmer JA, Toelle B, Celermajer DS, Marks GB. Lung function is associated with arterial stiffness in children. PLoS One 2011;6:26303.

20) Bhatt SP, Cole AG, Wells JM, Nath H, Watts JR, Cockcroft JR, et al. Determinants of arterial stiffness in COPD. BMC Pulm Med 2014;14:1.

21) Cheung YF, Brogan PA, Pilla CB, Dillon MJ, Redington AN. Arterial distensibility in children and teenagers: normal evolution and the effect of childhood vasculitis. Arch Dis Child 2002;87:348-51.

22) Greene ER, Lanphere KR, Sharrar J, Roldan CA. Arterial distensibility in systemic lupus erythematosus. Conf Proc IEEE Eng Med Biol Soc 2009;2009:1109-12.

23) Laurent S, Caviezel B, Beck L, Girerd X, Billaud E, Boutouyrie P, et al. Carotid artery distensibility and distending pressure in hypertensive humans. Hypertension 1994;23:878-83.

24) Mikola H, Pahkala K, Rönnemaa T, Viikari JS, Niinikoski H, Jokinen E, et al. Distensibility of the aorta and carotid artery and left ventricular mass from childhood to early adulthood. Hypertension 2015;65:146-52.

25) Quinones MA, Gaasch WH, Cole JS, Alexander JK. Echocardiographic determination of left ventricular stressvelocity relations. Circulation 1975;51:689-700.

26) Allen DH, Driscoll DJ, Shaddy ER, Feltes FT. Echocardiography. In: Moss and Adams’ Heart Disease in infants, Children and Adolescents. Philadelphia: Wlaters Kluwer/Lippincott, Williams & Wilkins; 2008. p. 128-31.

27) Nichols WW, O’Rourke MF, Avolio AP, Yaginuma T, Murgo JP, Pepine CJ, et al. Effects of age on ventricular-vascular coupling. Am J Cardiol 1985;55:1179-84.

28) Bouthier JD, De Luca N, Safar ME, Simon AC. Cardiac hypertrophy and arterial distensibility in essential hypertension. Am Heart J 1985;109:1345-52.

29) Lartaud-Idjouadiene I, Lompré AM, Kieffer P, Colas T, Atkinson J. Cardiac consequences of prolonged exposure to an isolated increase in aortic stiffness. Hypertension 1999;34:63-9.

30) Urschel CW, Covell JW, Sonnenblick EH, Ross J Jr, Braunwald E. Effects of decreased aortic compliance on performance of the left ventricle. Am J Physiol 1968;214:298-304.

31) Kelly RP, Tunin R, Kass DA. Effect of reduced aortic compliance on cardiac efficiency and contractile function of in situ canine left ventricle. Circ Res 1992;71:490-502.

32) Weber KT. Cardiac interstitium in health and disease: the fibrillar collagen network. J Am Coll Cardiol 1989;13:1637-52.