Abstract
Aims. In patients with hypertension (HT), increased aortic stiffness is related to higher cardiovascular morbidity and mortality. Recent investigations have shown that epicardial adipose tissue (EAT) is a new potential cardiometabolic risk factor. The aim of our study was to examine the relation between echocardiographically measured EAT thickness and aortic stiffness in patients with primary HT. Methods. The study included 144 newly diagnosed and untreated essential hypertensive outpatients. Transthoracic echocardiographic EAT thickness and aortic stiffness measurements were performed for all study participants. Afterwards patients were divided in two groups according to their median EAT thickness values. The patients with EAT thickness of < 7 mm were included in group 1 and patients with EAT thickness of ≥ 7 mm were included in group 2. Results. Aortic strain and distensibility parameters of group 2 were lower than in group 1. The aortic stiffness index of group 2 was found to be higher than group 1. Multivariate regression analysis revealed that EAT thickness was the only independent variable for all three parameters of aortic stiffness index, aortic strain and aortic distensibility. Conclusion. In patients with newly diagnosed primary HT, increased EAT thickness was significantly linked to impaired aortic elastic properties independently of other conventional adiposity measurements.
Key Words::
Introduction
The elastic properties of arteries, especially of the great arteries, play a crucial role in the hemodynamic balance of blood pressure (BP) (Citation1–3). Arterial stiffening is a cause of unfavorable hemodynamic alterations that increase cardiovascular morbidity and mortality (Citation1–4). In patients with hypertension (HT), studies have shown that increased aortic stiffness is an independent risk factor of developing atherosclerosis (Citation5), fatal stroke (Citation6), cardiovascular mortality and all-cause mortality (Citation7).
Epicardial adipose tissue (EAT) is visceral fat tissue, which has some protective effects on the heart through some biochemical and mechanical means (Citation8,Citation9). However, EAT may exert harmful effects owing to the fact that it is the source of pro-atherogenic and pro-inflammatory cytokines that can affect the cardiovascular system (Citation9–13). Recently, studies demonstrated that in hypertensive patients increased amount of EAT is associated with metabolic syndrome (Citation14), non-dipping circadian BP rhythm of HT (Citation15), higher level of BP (Citation12), impaired diastolic function (Citation10) and carotid arterial stiffness (Citation11). Until now, no study has examined whether EAT is linked to large arterial stiffness in patients with primary HT. In this study, we evaluated a hypothesis that these may be an association between EAT thickness and aortic stiffness, by using conventional echocardiography in patients with newly diagnosed untreated primary HT.
Methods
The study included 144 consecutive newly diagnosed untreated essential hypertensive patients. HT was defined as a systolic BP (SBP) of > 140 mmHg and/or a diastolic BP (DBP) of > 90 mmHg (mean of three measurements, at least two visits) (Citation16). Exclusion criteria were the presence of use of any antihypertensive medication, secondary HT, systemic inflammatory diseases, heart failure, severe valvular heart disease, renal failure and any history of coronary artery or cerebrovascular diseases. Demographic characteristics including age, gender, co-morbidities, smoking status, weight and height were noted. The local ethics committee approved the study protocol and informed consents were obtained from each of the study participants.
Anthromorphometric measures
Body mass index (BMI) was calculated as weight (kg) divided by the square of height (m2). To measure the waist circumference (WC), the tape was placed horizontally around the midpoint between the lower rib margin and the iliac crest, at the level of the umbilicus.
The echocardiographic examination
All patients underwent a comprehensive transthoracic echocardiographic study using 3.5-MHz transducer (Vivid 3 and Vivid 7, GE-Vingmed Ultrasound AS, Horten, Norway). All measurements were carried out according to criteria proposed by the American Society of Echocardiography guidelines (Citation17,Citation18). Echocardiographic examination was performed in the lateral decubitus position using standard parasternal long- and short-axis and apical views. Echocardiographic images including at least three consecutive beats were digitally stored and analyzed by an experienced cardiologist blinded to the subjects’ data.
The EAT was identified as a relatively hypo-echoic region between the right ventricular myocardium and the visceral layer of pericardium. EAT thickness was measured from parasternal long-axis view at end-systole, along the mid-line of the ultrasound beam and parallel to the aortic valve annulus plane, which was used as an anatomic marker (Citation13). The maximum thickness of epicardial fat at any site was measured. Reproducibility of EAT measurement was found to be excellent for intraobserver variability (intraclass correlation coefficient = 0.952, p < 0.001).
Determining the elastic properties of the aorta
The ascending aorta was recorded at a level of 3 cm above the aortic annular plane in the parasternal long-axis view and measurements were performed with M-mode tracing records. Aortic strain was established based on the relationship between changes in aortic diameter and BP with each cardiac pulse. Systolic diameter (SD) was measured as the maximal anterior motion of the aorta and diastolic diameter (DD) at the peak of the QRS complex of the simultaneously recorded electrocardiogram. Five consecutive cardiac beats were measured routinely and the average of the values was analyzed. The BP was simultaneously measured from the brachial artery with an external sphygmomanometer and was noted. Three aortic elastic parameters were calculated (Citation19):
where “ln” is the natural logarithm. The reproducibility of systolic and diastolic dimension measurements was analyzed with the intraclass correlation coefficient (ICC) test and reproducibility found to be good for intraobserver variability (ICC = 0.912 and 0.920, respectively, p < 0.001 for both dimensions).
Statistical analysis
All analyses were performed by using SPSS 17.0 statistical software (SPSS Inc., Chicago, IL, USA). To test the distribution pattern of continuous variables, the Kolmogorov–Smirnov test was used. Data were given as the mean± standard deviation, medians and interquartile range, or proportions. Student's t-test was used to compare groups’ data displaying normal distribution. Mann–Whitney U test was applied to compare the data without normal distribution. Chi-square test was used for categorical variables. To evaluate the relationships between aortic stiffness parameters and the other significant variables, univariate and stepwise multivariate linear regression analyses were performed. Entry into the regression model required a p-value of < 0.10. For all tests, statistical significance was accepted as p < 0.05.
Results
According to the median value of the EAT thickness, the patients were assigned into two groups: EAT < 7 mm (group 1, n = 74) and EAT ≥ 7 mm (group 2, n = 70). The baseline demographic and clinical data of the groups were presented in . Those patients in group 2 tended to be older; moreover, BMI and WC were higher than those in group 1. No difference was observed between the groups with respect to the clinical systolic or diastolic BP values. The patients’ echocardiographic data including aortic stiffness parameters are given in . In patients with group 2, the mean aortic strain and distensibility values were significantly lower than group 1 (11.5 ± 3.7% vs 7.8 ± 3.7%; p < 0.001 and 7.6 ± 2.0 10 − 6 cm2/dyn vs 6.0 ± 2.2 10 − 6 cm2/dyn; p < 0.001) ( and ). Aortic stiffness index was higher in group 2 compared with group 1 (6.5 ± 0.6 vs 5.7 ± 0.9; p < 0.001) (). Regression analysis describing the relation between EAT and aortic stiffness are presented in . Stepwise multivariate logistic regression analysis revealed that only EAT thickness was independently associated with all of aortic stiffness index, aortic distensibility and aortic strain. Beside this, age was found to be independently associated with aortic strain and aortic stiffness index and BMI was independently related to aortic strain.
Figure 1. Aortic strain according to epicardial adipose tissue (EAT) thickness.
Figure 2. Aortic distensibility according to epicardial adipose tissue (EAT) thickness.
Figure 3. Aortic stiffness index according to epicardial adipose tissue (EAT) thickness.
Table I. Baseline demographic and clinical data of the groups.
Table II. The echocardiographic data of the patients.
Table III. Univariate and stepwise multivariate linear regression analysis of aortic stiffness parameters in patients with hypertension.
Discussion
In the current study, we investigated the relation between EAT thickness and aortic stiffness by using non-invasive echocardiographic methods in newly diagnosed untreated hypertensive subjects. Our results suggest that there is an independent and strong relationship between EAT thickness and aortic stiffness indices in patients with primary HT.
Arterial stiffness is a common entity that describes the rigidity of the arteries and structurally it is characterized by several changes in the extracellular matrix of the arterial wall (Citation1–4). The elastic properties of the arterial wall are determined by near constant proportions of two major proteins consisting of elastin and collagen (Citation20). Dysregulation of these proteins results in increased pulse wave velocity and arterial stiffness. There are many hemodynamic effects of arterial stiffening on the cardiovascular system, such as increased central pulse pressure and systolic BP, high ventricular load and left ventricular hypertrophy, increasing myocardial oxygen demand and impaired myocardial perfusion (Citation1–4). Moreover, arterial stiffness impairs the microcirculation of small vessel of vital organs such as brain, heart and kidneys (Citation21). Therefore, arterial stiffness is emerging as an important risk factor for dementia, HT, stroke, renal failure, myocardial infarction and mortality (Citation3,Citation5,Citation6,Citation21,Citation22).
Although HT itself is a significant cause of mortality, even in hypertensive subjects, the mortality rate can be staged by severity of aortic stiffness. In a study conducted on 1980 essential hypertensive patients, researchers demonstrated that increased aortic stiffness was significantly associated with both cardiovascular and all-cause mortality, independent of age, diabetes and other cardiovascular disorders (Citation7). In another large and longitudinal study, Laurent et al. (Citation6) reported that aortic stiffness is an independent predictor of fatal stroke in patients with primary HT. In the Rotterdam study, which included both normotensive and hypertensive subjects, van Popele et al. (Citation5) investigated whether arterial stiffness was a risk factor for developing atherosclerosis independent of conventional risk factors. In this population-based study, the researchers found that after adjustment of data for age, sex, mean arterial pressure and heart rate, increased arterial stiffness was independently and strongly related to atherosclerosis at different sites of body.
Nowadays, the issue of epicardial fat attracts the attention of investigators and scientific data of this topic is rapidly growing. The EAT embryologically is linked to visceral adiposity and it carries characteristic properties of visceral lipoidosis (Citation9,Citation13,Citation23). Hence, as well as other visceral fat depots, EAT acts as a metabolically active endocrine organ that expresses many biologically active molecules and proinflammatory, proatherogenic cytokines. Another important property of EAT, in which it differs from other visceral fat tissues and which makes it more dangerous, is that, because of its close neighbors, it can interact locally with the coronary arteries and the myocardium through paracrine and/or vasocrine pathways (Citation8,Citation9). Recent investigations showed that increased thickness or volume of EAT is significantly related to insulin resistance, increased cardiometabolic risk, inflammatory markers, coronary artery disease and HT (Citation8,Citation9). The effect of epicardial fat depots on arterial stiffness has been investigated in various studies, including both normotensive and hypertensive individuals. Natale et al. (Citation11) reported that increased EAT reflects carotid artery stiffness in patients with primary HT. In asymptomatic subjects, Park et al. (Citation24) showed that among different adiposity types EAT was the strongest adiposity type, which correlated with arterial stiffness measured by cardio-ankle vascular index. In a study that included consecutive 655 outpatient subjects, Kim et al. (Citation25) demonstrated that echocardiographic EAT thickness was independently linked to brachial–ankle pulse wave velocity measured aortic stiffness (Citation25). In another study, which included 128 consecutive outpatients, Choi et al. (Citation26) showed that increased EAT volume was linked to vascular stiffness, which was documented with carotid–radial pulse wave velocity. Although the relationship between EAT and increased arterial stiffness was demonstrated in aforementioned studies, studies that investigate the effect of EAT thickness on aortic stiffness in patients with newly diagnosed untreated primary HT have not yet been performed. Herein, we reported that in patients with HT increased EAT thickness was associated with impaired aortic elasticity independently of other factors including age, WC, BMI and office systolic BP value. There was statistically significant relation between echocardiographically measured EAT thickness and aortic elasticity indices. To the best of our knowledge, this is the first study of the influence of epicardial fat on aortic stiffness in patients with primary HT.
Studies showing the negative impact of EAT on cardiovascular outcomes suggest that this relationship would be due to the fact that EAT acts as a source of inflammatory mediators (Citation8,Citation9,Citation27). Indeed, EAT aggravates the inflammation in neighborhood tissues like myocardium and coronary arteries, and in systemic circulation by virtue of many mediators, such as tumor necrosis factor alpha, monocyte chemoattractant protein-1, resistin, interleukin-6, interleukin-8, interleukin-1b and plasminogen activator inhibitor-1 (Citation9). Arterial stiffness is largely dependent on the structural properties of the large artery wall, and high inflammatory state is one of the reasons for impaired aortic elastic properties (Citation4,Citation19). It has been shown that inflammation is associated with increased arterial stiffness in a variety of settings (Citation4,Citation19,Citation27,Citation28). Pro-inflammatory activity and cytokine secretion from EAT may promote inflammation in the blood vessel wall, which may lead to aortic stiffness (Citation4,Citation19,Citation28). Although our data did not support the relationship between increased EAT thickness and increased inflammatory state with inflammatory markers, we can explain the relationship between increased EAT thickness and increased aortic stiffness by the action of EAT as a pro-inflammatory fat tissue.
Study limitations
One of our study limitations was the fact that the study was a cross-sectional design, instead of a prospective design. We observed significant association between increased EAT thickness and aortic stiffness; however, we could not clarify the underlying exact mechanism responsible for this finding. Although we suggested that the relationship between increased EAT thickness and increased aortic stiffness would be explained by the fact that EAT acts like a pro-inflammatory fat tissue, we did not evaluate any inflammatory markers in our present study. Additionally, in our study, stiffness indexes were calculated only by using brachial blood pressure values and echocardiographic data. However, further evolving techniques including applanation tonometry, oscillometric methods and cardiac magnetic resonance imaging may also be used in the calculation of aortic stiffness indexes.
Conclusions
In patients with primary HT, increased echocardiographic EAT thickness was independently related to aortic stiffness.
Declaration of interest: The authors declared no conflict of interest.
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