Milan, Alberto; Tosello, Francesco; Naso, Diego; Avenatti, Eleonora; Leone, Dario; Magnino, Corrado; Veglio, Franco
Aortic root dilatation is a common clinical feature in hypertensive patients (10%) . The vast majority of data in literature [1,2] refers to dilatation of the first aortic segment, known as sinus of valsalva (SoV) that is routinely evaluated during a standard echocardiographic examination. SoV dilatation has been shown to be related to hypertension-induced organ damage, and in particular to cardiac damage (i.e. left ventricular hypertrophy) . Moreover, SoV dimensions, especially when increased, are associated to increased values of parameters describing central hemodynamic [4,5], but not to increased arterial stiffness as expressed by pulse wave velocity (PWV).
The second tract of the aortic root, the proximal ascending aorta (pAA), can undergo dilatation as well. Nevertheless, even if it can be evaluated through echocardiography, few data have been published evaluating patients with this specific phenotype. Roman et al. observed the association between age and aortic dimensions to be stronger when considering ascending aorta  instead of SoV and it has been reported a faster growth progression of the ascending aneurysm in younger patients.
It is not known whether pAA dilatation may be related to increased left ventricular mass (LVM) and what the relation with central hemodynamics and arterial stiffness would be. Aims of the present study were then, first, to evaluate pAA dilatation prevalence in essential hypertensive free from other associated clinical condition and describe such a phenotype in terms of central and peripheral hemodynamic, arterial stiffness and LVM; second, to evaluate possible differences between such patients and the better studied ones showing SoV dilatation.
We evaluated 345 adult outpatients with consecutive essential hypertension who were referred to the echo laboratory of the Hypertension Unit, University of Turin for target organ damage evaluation. All the evaluations were done in the same day.
For recruitment, all individuals underwent a full medical examination. All blood pressure measurements were performed according to the European Society of Hypertension/European Society of Cardiology (ESH/ESC)  recommendations. Hypertension was defined by SBP at least 140 mmHg and/or DBP at least 90 mmHg on three consecutive occasions or by the assumption of antihypertensive medications.
Exclusion criteria were age less than 18 or more than 70 years, BMI at least 40 kg/m2, secondary hypertension, nonhypertensive cardiovascular disease, any valvulopathy more than mild, bicuspid aortic valve, diabetes, presence of associated clinical conditions as defined by the ESH/ESC  guidelines, family history of aortic rupture, clinical characteristics suggesting a genetic predisposition to aortic disease such as Marfan syndrome.
The study was approved by our Institutional Review Committee and all participants provided their written informed consent (CEI/330).
Arterial stiffness and wave reflection measurements
Blood pressure and heart rate were measured three times, at 2-min intervals using a validated automatic oscillometric device (Omron Matsusaka Co., Ltd., Mie, Japan). The mean value from these three measurements was used for further analysis. PWV, a classic index of arterial stiffness was measured along the descending thoracoabdominal aorta by the foot-to-foot velocity method, as previously published and validated . Briefly, waveforms were obtained transcutaneously over the common carotid artery and the femoral artery and the time delay (t, in second) was measured between the feet of the two waveforms. The distance (D, in metres) was divided by the delay time, so that PWV was calculated as the following:PWV = D/t
The Sphygmocor system (AtCor Medical, Sydney, Australia) was used on the day of the echocardiography assessment and after an overnight fast.
Augmentation index and ‘central’ blood pressure parameters
Radial artery waveforms were obtained with a high-fidelity micromanometer (SPC-301; Millar Instruments, Houston, Texas, USA) from the wrist and a corresponding central waveform was generated with a validated transfer function (Sphygmocor) as previously described in detail and validated [10,11]. Calibration of the radial arterial waveform obtained by applanation tonometry was carried out with SBP and DBP values recorded noninvasively. DBP and mean arterial pressure were assumed to remain constant throughout the arterial tree .
Augmentation pressure was the height of the late systolic peak above the inflection. The aortic or central augmentation index (AIx) was calculated as the ratio of the pressure difference between the ‘shoulder’ of the pressure wave and ‘peak’ systolic pressure (ΔP)  and the pulse pressure (PP) according to the following formula:
Equation (Uncited)Image Tools
Central PP (cPP) was calculated as the difference between the estimated aortic systolic and diastolic pressures . PP amplification (PPamp) ratio was calculated as the ratio of peripheral to cPP.
A two-dimensional echocardiogram was performed at rest in the left lateral decubitus position with commercially available ultrasound systems (ATL 5000; Bothell, Washington, USA). Multiple-frequency phased array transducers (2–4 MHz) were used.
Technical details have been reported previously . Briefly, the LVM was estimated from the end-diastolic left ventricular internal diameter (LVIDd), interventricular septum and inferolateral wall thickness (ILW) by Devereux's formula  and was normalized to height2.7. Relative wall thickness (RWT) was calculated as the following:
Equation (Uncited)Image Tools
Patterns of left ventricular geometry were defined according to ESH/ESC  recommendations. Left ventricular hypertrophy was defined as LVM indexed for height2.7 greater than 46.7 g/m2.7 in women or greater than 49.2 g/m2.7 in men .
BSA was calculated using the following Dubois and Dubois formula:
Equation (Uncited)Image Tools
Images of the proximal aortic root were obtained from a parasternal long axis view. Aortic size was measured using two-dimensional echocardiography as the maximal distance between the two leading edges of the anterior and posterior aortic root walls at end diastole . Two sites of the proximal aorta were considered: the SoV, usually called aortic root, and the ascending aorta. pAA was measured between 2 and 6 cm above the aortic valve closure at its maximum width. All aortic diameters were normalized to the BSA for the analysis, as described above.
Considering current literature , aortic dilatation was defined as aortic dimension indexed for BSA more than 2.1 cm/m2. The population was then divided in two groups (i.e. with/without pAA dilatation); subsequently, dilatation of SoV was considered, and patients with this phenotype were compared to patients showing pAA dilatation.
Statistical analysis was conducted using SAS V8 software (SAS Institute Inc., Cary, North Carolina, USA). The parametric distribution of the variables was analyzed using the Kolmogorov–Smirnov test and residual analysis. Data are expressed as mean ± SD or as median and interquartile difference if appropriate. Differences between means were examined using a Student's t-test or ANOVA for normally distributed variables. Kruskal–Wallis or nonparametric ANOVA were used for nonnormally distributed variables.
Multiple regression analyses were used to assess the independent determinants of aortic dimensions. Independent variables were selected based on their known or expected association with aortic dimensions.
Statistical significance was assumed if the null hypothesis could be rejected at P value less than 0.05.
Table 1 shows clinical features of patients with ascending aorta dilatation compared with individuals with normal pAA. Prevalence of pAA dilatation was 17%.
Absolute ascending aortic dimensions were significantly correlated to age (r = 0.42; P < 0.0001), BMI (r = 0.28; P < 0.0001) and peripheral diastolic pressure (r = 0.13; P = 0.01). After correction for BSA, the correlation with BMI was no longer detectable, but the one with age was even stronger (r = 0.54; P < 0.0001). Peripheral hemodynamic parameters (Table 1) were similar in patients with and without pAA dilatation. Patients having pAA dilatation were an average 10 years older and dilatation was more often seen in women (prevalence 24 vs. 16%; P < 0.05).
We observed a greater prevalence of active drug treatment (100 vs. 79.2%; P = 0.01) and a greater number of antihypertensive drugs (2 ± 0.97 vs. 1.45 ± 1; P = 0.007) in patients with ascending aorta dilatation; nevertheless, prevalence of different classes of drugs used was similar in the two groups. Considering central hemodynamic parameters (Table 2), we observed a significant increase of systolic and PP, whereas diastolic pressure and mean pressure, were similar. PWV was significantly greater (9.26 ± 2.3 vs. 7.7 ± 1.7 m/s; P < 0.0001), as well as the AIx, both when considering absolute (30 ± 10.5 vs. 22.7 ± 10; P < 0.0001) and heart rate indexed (25.9 ± 10 vs. 19.4 ± 9; P < 0.0001) values. The PPamp ratio was significantly lower in patients with aortic dilatation (124 ± 11 vs. 134.5 ± 15; P < 0.0001), suggesting a greater arterial stiffness in such a group. Considering echocardiographic variables (Table 2), patients with pAA dilatation showed a significant increase of LVM (P < 0.0001) compared to patients with normal aorta.
Left ventricular hypertrophy was thrice as frequent compared to hypertensive patients free from aortic dilatation; the RWT was significantly increased as well (0.43 ± 0.10 vs. 0.40 ± 0.07; P = 0.01).
Patients with pAA dilatation showed significantly increased dimensions of SoV compared to the control group (3.9 ± 0.5 vs. 3.7 ± 0.5 cm; P < 0.0001).
Taken together, these data suggest a strong association between pAA dimensions (in particular when indexed for BSA) and hypertension-related organ damage, in terms of both increased LVM and arterial stiffness (Fig. 1).
As stated, the study population comprehended mainly male participants (75%), but the prevalence of pAA dilatation was significantly greater in the female sex (24 vs. 16%; P < 0.05).
Male and female patients had similar age and mean pressure. Male individuals had, in average, a greater systolic (133.6 ± 16.7 vs. 139 ± 15 mmHg; P = 0.01) and PP (52.7 ± 11.7 vs. 56.6 ± 10.6 mmHg; P = 0.005). Echocardiographic features such as LVM indexed for BSA and atrial dimensions were similar. Considering central hemodynamic parameters, we observed similar PWV and central pressures (systolic, diastolic and PP), but a clear and statistically significant increase of AIx in the female population (29.5 ± 8.6 vs. 18.1 ± 8.8; P < 0.0001), together with a lower PPAmp index (122.3 ± 10.1 vs. 135.4 ± 15.1; P < 0.0001).
Considering only patients with pAA, the two subgroups (men vs. women) had similar characteristics with the only exception, again, of the AIx (34.78 ± 10.74 vs.22.13 ± 7.31; P < 0.0001) significantly greater in women, and the PPAmp index (117.6 ± 6.74 vs.126.76 ± 11.33; P < 0.0001) greater in the male population.
Ascending aorta vs. sinus of valsalva dilatation
The second part of the study focused on highlighting differences between dilatation involving ascending aorta and SoV. Patients were then divided in four subgroups: normal aortic dimensions (group A), SoV dilatation alone (group B), pAA dilatation alone (group C) and dilatation of both segments (group D). Clinical features are summarized in Table 3.
Dilation of SoV alone was present in 15.9% of patients, whereas individuals with pAA dilatation were 11%, and 6.7% of the individuals showed a dilatation involving both segments. Patients with isolated dilatation of SoV (group B) and patients with normal aortic dimensions had very similar clinical features.
Hypertensive patients with lone pAA dilatation were averagely older, with a significant prevalence of female sex, like patients in group D with combined dilatation of SoV and pAA. Other clinical features were substantially similar to those of other groups.
Left ventricular hypertrophy had a prevalence of 14% both in the group with SoV dilatation and in the group of patients with normal aortic dimensions, whereas the prevalence was significantly higher in the subgroup of patients with pAA dilatation, with (39%) or without (28%) associated dilatation of SoV.
Evaluating arterial stiffness parameters, the subgroup of patients with pAA dilatation showed significantly increased PWV values (e.g. 9.0 ± 1.7 vs. 7.7 ± 2.1 m/s; P < 0.0001) compared to patients without pAA enlargement. These data were confirmed even after correction for possible confounding variables such as age (data not shown).
Considering central hemodynamic parameters, a significant increase of cPP and AIx was detectable in patients with pAA dilatation. Patients with isolated pAA dilatation had a significant increase of AIx and a similarly significant decrease of PPamp ratio when compared to other groups, and the difference was statistically relevant even when comparison was made with patients affected by dilatation of both SoV and pAA (Table 4).
Focusing our attention on the SoV dilatation group only, we observed that patients had central pressure values comparable to the ones of hypertensive patients free from aortic dilatation, but a significant increase of PPamp ratio compared to all groups.
Lastly, we evaluated possible independent predictors of aortic dimensions. The performed multiple regression analysis included clinical (age, sex, BMI), hemodynamic (pPP, cPP) and echocardiographic (LVMi) parameters, as well as parameters describing arterial stiffness (PWV, AIx, PPAmp index). We tested apart the different aortic segments (pAA and SoV) considering both absolute and indexed values. We observed that age (e.g. β ± standard error 0.17 ± 0.02; P < 0.0001) and LVM (0.11 ± 0.02; P < 0.0001) are significantly associated to absolute and indexed aortic root dimensions, both considering pAA and SoV.
PWV (0.51 ± 0.14; P = 0.0005), a strong index of arterial stiffness, was significantly associated to dimensions of pAA, but not to SoV diameters (−0.11 ± 0.14; P = 0.4045).
In order to evaluate independent association between arterial stiffness and proximal aortic dimension (SoV or pAA), we divided the population into tertiles of PWV (first group <7 m/s, third group ≥8.4 m/s). We observed a significant difference between the first (mean pAA ± standard error, age weighted, 3.4 ± 0.5 cm), the second (3.6 ± 0.5 cm, P < 0.001) and the third tertile (3.8 ± 0.5 cm). Similar results were obtained using BSA-weighted pAA, whereas absolute and indexed values of SoV dimensions were similar in the three groups (P = n.s.).
The main findings of this study are as follows: first, ascending aorta dilatation is a common phenotype in hypertensive patients, being present in up to 17% of our study population; second, ascending aorta dilatation is associated with significant left ventricular hypertrophy and with a significant increase in arterial stiffness; lastly, hypertensive patients with SoV dilatation alone (16% of our population), namely without associated dilatation of ascending aorta, show benign features in terms of LVM and arterial stiffness, similar to those of essential hypertensive with normal aortic dimensions. Taken together, these data suggest the dilatation of the ascending aorta as a key point in the identification of patients with a significant increase of organ damage, and, likely, of cardiovascular risk.
Prevalence and clinical features
Dilatation of proximal aorta (SoV, ascending aorta or both) represents a clinical phenotype with high prevalence in our group of hypertensive patients. One-third of the patients had at least mild dilatation in one of the considered sites (SoV, ascending aorta or both). SoV dilatation has been studied in hypertensive patients with a prevalence ranging from 4.2  to 11% ; in our population SoV dilatation (alone or in combination with ascending aorta dilatation) was twice as common (22%). This result may be due to a referral bias or to a greater sensitivity of the applied criteria for definition of aortic root dilatation. As suggested by current European recommendations  the present study used, a single, BSA-indexed cut off, against the absolute values of aortic diameter, frequently used in published studies . Such a difference, if confirmed, would indicate a potential under diagnosis of SoV dilatation due to the lack of adjustment for BSA in the specific subgroup of patients with low BSA and small linear dimensions.
To the best of our knowledge, no data were previously reported on the prevalence of dilatation of proximal aorta in uncomplicated essential hypertensive.
In our population, 11% of patients showed dilatation of the ascending aorta, with normal SoV. This finding suggests that ascending aorta evaluation should be routinely performed during a standard echocardiographic examination in the hypertensive patient.
Some anthropometric variables such as age, sex and BSA have been shown to be strictly related to aortic dimensions. It is well known that aortic aging is characterized by loss of elastic vessel properties that determines aortic remodeling and dilatation . In our population, patients showing aortic dilatation were on average 10 years older than patients with normal aortic dimensions. Moreover, our data confirm [7,21] the association between SoV, age and body surface, already described in different patients populations. Such an association remains considering not only SoV, but ascending aorta diameters as well. The thigh association with height and weight underlines the importance of regularly applying BSA indexation when analyzing aortic dimensions.
We observed a high female prevalence (43%) in the group of patients with isolated dilatation of the ascending aorta. Few data are present in literature [7,22,23] regarding thoracic aortic aneurysm and they show that aortic dissection has a worse prognosis in female patients . Our finding supports the importance of early identification of female patients with pAA dilatation as potentially carrying a higher dissection risk.
Furthermore, the group of patients with dilatation of the ascending aorta showed a significant increase of central hemodynamic parameters. In particular, women with ascending aorta dilatation, when compared to men, had a significant increase of AIx, with a parallel, significant reduction of great vessel elasticity, as described by a reduced PPamp ratio. It has been recently hypothesized that the demonstrated increased AIx in female patients could be associated to greater risk of developing normal ejection fraction heart failure . Our data confirm the association between female sex and AIx ; in particular, increased AIx in patients with enlarged ascending aorta could identify a greater susceptibility of such a subgroup in developing cardiovascular diseases.
Ascending aorta dilatation, left ventricular hypertrophy and arterial stiffness
Ascending aorta dilatation in our population was strictly associated with increased cardiac (left ventricular hypertrophy) and vascular (arterial stiffness) organ damage.
In the past [1,3,19], a significant association has been observed between SoV dilatation and LVM, and this has been confirmed in our study. However, our data show that only when a dilatation of SoV is coupled with a similar dilatation of the ascending aorta, a significant increase in LVM is detectable. With a selective dilatation of SoV, prevalence of left ventricular hypertrophy is similar to the one observed in hypertensive patients with normal aortic dimensions. Dilatation of the ascending aorta would then be a stronger marker of hypertension-induced organ damage. Confirmatory in this hypothesis is the association we found between ascending aorta dimensions and PWV.
PWV is a well known marker of cardiovascular risk [26,27], as a index of arterial tree aging . Sugawara et al., using MRI, showed that elongation of ascending, but not of descending, aorta was directly associated to PWV increase even in apparently healthy individuals. Our study suggests that in hypertensive patients, for an increase in ascending aorta dimensions might occur a parallel loss of the elastic properties of the vessel, as shown by a direct and independent increase of the measured PWV.
The present results indicate a high prevalence of ascending aorta dilatation in essential (uncomplicated) hypertensive patients. Furthermore, the dilatation of the ascending aorta is associated to an increased left ventricular hypertrophy and, similarly, to an increased arterial stiffness.
On this basis, the evaluation of ascending aortic tract should be part of the routine echocardiographic examination for the hypertensive patient in order to avoid a missed diagnosis of aortic dilatation and grant a better patients’ risk stratification.
Conflicts of interest
There are no conflicts of interest.
Reviewers’ Summary Evaluations Referee 1
The study by Milan et al. shows that in (essential) hypertensive patients with increased aortic stiffness (increased PWV) ascending aortic diameter dilatation and that this dilatation is often seen relates with LVM.
The article's strength is that increased ascending aorta dilatation could imply a lower aortic characteristic impedance (Zc), and thus a slower initial rise in aortic pressure and smaller ventricular wall stress, thereby limiting hypertrophic pathways.
The weakness of the paper is that other authors have shown that with hypertension aortic diameter decreases (Circulation 2003;108 : 1592) and that Zc may not change in hypertension (J. Hypertens 2012;30 : 1493).
Left ventricular hypertrophy (LVH) and arterial stiffness have long been associated as either the consequence or cause of systemic hypertension. Although proximal aortic dilatation has also been associated with systemic hypertension, the authors of this manuscript state that the co-existence of these three features has not been previously reported.
In this study, they found proximal aortic dilatation in 17% of 345 untreated hypertensives and noted an association with both LVH and arterial stiffness. Whether aortic dilatation contributes to aortic valvular incompetence was not addressed in this cross-sectional study and would require long follow-up.
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