Observational study of regional aortic size referenced to body size: production of a cardiovascular magnetic resonance nomogram

447 healthy adult volunteers (male, n = 208) between the ages of 19 and 70 years without identifiable cardiovascular risk factors, were recruited to studies within the University Oxford Centre for Clinical Magnetic Resonance Research (OCMR). Subjects were grouped according to gender and World Health Organisation body mass index (BMI) categories: normal (BMI 18.5-25), overweight (BMI 25–30), obese (BMI >30), male; normal weight (55%), overweight (31%), obese (14%), female; normal weight (56%), overweight (19%), obese (25%). All subjects underwent CMR at 1.5 Tesla for the assessment of regional aortic diameter. All studies were approved by the local research ethics committee (Oxfordshire Research Ethics Committee, and informed written consent was obtained from each participant.

All subjects were screened for the presence of identifiable cardiovascular risk factors and were excluded if they had a history of; cardiovascular disease, cardiac chest pain, hypertension, diabetes, smoking, use of prescription medications or were pregnant or under 18 years of age (age range 18 – 80 yrs). Body mass index (BMI) in (kg/m²) was calculated as a simple measure of obesity using the formula weight (kg)/height(m²) and body surface area (BSA) in m² was calculated using the Du Bois formula BSA (m²) = 0.20247 × Height(m)^0.725 × Weight(kg)^0.425.

Fasting blood tests for glucose and cholesterol were taken on the day of the scanning and analysed as previously described[23].

A normal blood pressure was taken as an average of three supine measures over ten minutes under 140/90 mmHg, (Model, DINAMAP 1846-SX, Critikon Corp).

Imaging was performed on a 1.5 Tesla MR system (Siemens Avanto, Erlangen, Germany). All imaging was retrospectively cardiac gated with a precordial three lead ECG and acquired during end expiration breath hold. Oblique sagittal pilot, half-Fourier single shot turbo spin echo (HASTE) images were followed by steady-state free precession (SSFP) cine images with the following parameters: echo time of 1.12 ms, repetition time of 39 ms using 15 segments and 25 phases, slice thickness of 7 mm and pixel size of 2 mm × 2 mm. Cross sectional images, of the aorta were obtained orthogonal to the sagittal oblique scout at three pre-determined points; the ascending aorta (Ao) and descending aorta at the level of the pulmonary artery (PDA) together with the descending aorta 12 cm distal to the pulmonary artery (DDA) (Figure 1(i))[13].

Anthropometric data for the study groups are shown in Table 1. All subjects were normotensive at the time of scanning. Both male and female groups in each BMI category were well-matched for age, MI, diastolic blood pressure (DBP), systolic blood pressure (SBP), fasting glucose and fasting cholesterol level (all analyses p >0.05) with all values within the normal adult range. Both SBP (♂ 119 ± 11 vs. ♀ 117 ± 11 mmHg, p = 0.02) and DBP (♂ 73 ± 8 vs. ♀ 71 ± 8 mmHg, p =0.01) were statistically higher in males, but still well within the normal blood pressure range. As expected, increasing BMI was associated with an increase in both systolic and diastolic blood pressure ♂ SBP; r = 0.28, DBP; r = 0.29, ♀ SBP; r = 0.21, DBP; r = 0.18, all p <0.01).

On grouped analysis, the mean and normal range (calculated as mean ± 2 SD) for each aortic plane across the whole population were calculated independently for male and females as follows; AV annulus male (♂) 24.4 ± 5.4, female (♀) 21.0 ± 3.6 mm, aortic sinus ♂32.4 ± 7.7, ♀27.6 ±5.8 mm, STJ ♂25.0 ± 7.4, ♀21.8 ± 5.4 mm, Ao ♂26.7 ± 7.7, ♀25.5 ± 7.4 mm, PDA ♂20.6 ± 5.6, ♀18.9 ± 4.0 mm, DDA ♂17.6 ± 5.1, ♀16.4 ± 4.0 mm. A graphical representation of the gender-specific normal range data for regional aortic diameter indexed to BSA according to age is presented as a nomogram in Figure 2 (Male) and Figure 3 (Female), while gender-specific normal range data for regional aortic diameter according to BMI group is presented in Table 2.

With the exception of the aortic valve annulus, which was not affected by increasing age (p > 0.44 for males and females), all other aortic measurements increased with increasing age (Tables 3 and2, Figures 2 and3). However, increasing age, in the absence of hypertension and other vascular risk factors, was associated with only a small change in aortic size (♂;+1.0 -1.9 mm, ♀; +0.7 – 1.5 mm per decade of increasing age). Whereas the aortic sinuses, ST junction and ascending aorta showed no gender difference in the degree of dilatation with increasing age, p > 0.16 for all analyses (Table 4), males showed a greater degree of dilatation of the proximal descending (♂; +1.4 mm vs ♀; +0.8 mm per decade ↑age, p <0.001) and abdominal aorta (♂;+1.4 mm vs ♀; +1.1 mm per decade ↑age , p <0.02, Figure 2).

In both males and females on linear regression analyses, BMI and BSA were positively correlated with all aortic diameters with the exception of the aortic sinuses, where BMI was not related to diameter (both genders; p > 0.06, Table 1). Interestingly, the degree of dilatation with increasing obesity was small, (♂;+1.4 – 2.1 mm, ♀; +0.8 – 1.7 mm per 10 kg/m² increase in BMI). In general, the degree of aortic dilatation with increasing BMI and BSA was not significantly different between men and women at all levels measured (p > 0.10 for all analyses except for the level of the PDA, Table 4, Figures 2 and3). To account for the effect of age, height and SBP, all known to increase aortic size and positively correlated with diameter in this study, an adjusted model was performed. This showed that after adjusting for age, height and SBP, the positive relationship between aortic diameters and both BMI and BSA remained unchanged (data not shown).

Again, with the exception of the aortic sinuses, all regional aortic diameter measures were positively correlated with both BMI and BSA (data not shown), with the degree of dilatation remaining small (♂;+0.5 – 1.2 mm, ♀; +0.7 – 1.2 mm per 10 kg/m² increase in BMI). Again, no gender differences in the degree of dilatation with increasing BMI and BSA was seen when adjusting for systolic blood pressure, age and height.

In males and females, the largest increase in aortic size with increasing body size was at the level of the ascending aorta (♂ + 7.6, ♀ + 5.6 mm per m² BSA increase, both p <0.01) with a smaller effect seen in the more distal proximal descending (♂ + 5.5, ♀ + 2.8 mm per m² BSA increase, both p <0.01) and abdominal aorta (♂ + 3.8, ♀ + 3.1 mm per m² BSA increase, both p <0.01). Interestingly, the effect of stroke volume increase on aortic diameter increase was also greatest in the ascending aorta (♂ + 6.5, ♀ + 3.6 mm per 10 ml increase in LV stroke volume, both p <0.01) when compared to the abdominal aorta (♂ + 3.7, ♀ + 2.4 mm per 10 ml increase in LV stroke volume, both p <0.01). Importantly, as expected, obesity was positively correlated with stroke volume (r = 0.21, p <0.001). This suggests that increased stroke volume may be accounting for at least some of the increase in proximal aortic diameters seen.

For aortic root analysis, intra-observer variability of ±0.7% (0.19 mm) was determined by blinded, repeat analysis of 15 scans (45 measurements, 5% of the study cohort) undertaken 1 week following the initial analysis. Inter observer variability was performed on the same cohort, the inter-observer variability was ±1.34% (0.36 mm). In the other regions aortic cross sectional diameter was calculated using a semi-automated in house software program within Matlab 6.5©, which results in a highly reproducible assessment of area, and more reproducible than manual contouring techniques, the coefficient of variance for the automated image analysis technique is 0.58%[26].

Both cardiac output and total blood volume are elevated with increased BSA, and studies have shown that these circulatory changes result in left and right ventricular hypertrophy and cavity dilatation[3, 27]. As a result of this increased stroke volume, it might be expected that obesity and increased BSA would be associated with an increase in aortic size, and previous studies using both CMR and echocardiography have confirmed that aortic root size is larger in obese when compared to normal weight subjects[10, 28]. However, these studies have not excluded patients with hypertension and other cardiovascular risk factors that can be present in obesity and known to be independently linked to increased aortic size. As such the effect of increased BSA per se is not well understood. Using a large population of subjects, free from hypertension and other vascular risk factors, this study not only shows that increasing BSA and BMI, without comorbidity, is associated with increasing aortic size but also, interestingly, that the degree of dilatation in the absence of hypertension is modest, between 1.4 – 2.1 mm (males) and 0.8 – 1.7 mm (females) per 10 kg/m² BMI point increase. This would suggest that if significant aortic dilatation is present in obesity, is unlikely to be attributable to obesity alone, and a second pathological process should be sought. As expected, males had larger aortic measurements than females. However, there was no gender difference in the degree of dilatation with increasing BMI or BSA.

Interestingly, the effect of increasing BSA on aortic size seems to be most pronounced in the aortic root and ascending aorta, with a smaller effect seen distally. This pattern is the mirror image of increased aortic stiffness seen in obesity, which is more pronounced in the abdominal aorta than the ascending aorta[29], and may be explained by the proximal aorta being more directly exposed to the increased stroke volume accompanying larger fat mass and therefore showing the largest change in size, in line with its 'Windkessel’ function. In support of this, not only were aortic diameters positively correlated with left ventricular stroke volume, but also the largest effect was seen in the ascending aorta. In contrast to this, volumetric changes would not be expected alter aortic elastic function, and the changes in abdominal aortic stiffness in obesity have been proposed to be related to elevated levels of adipokines and free fatty acids[30, 31].

In line with other published data,[32] increasing age was associated with modest increase in aortic size. This may be explained by the age-related increases in collagen synthesis that occur with advancing age, potentially leading to dilatation[33]. Whereas proximal sections (up to and including ascending aorta) show no gender difference in rate of dilatation with advancing age, this study has, however, shown that the more distal aortic regions (proximal descending and abdominal aorta) have significant gender differences in the degree of dilatation with advancing age, with males exhibiting up to a 43% greater dilatation than females. The reasons for this gender difference is unknown, but given the higher rate of abdominal aneurysm formation in men[34] this is an interesting finding, worthy of further study.

Aortic sinus measurements made on this study were similar to a previous echocardiography study by Wolak et al., of 1207 subjects over 15 yrs of age[11]. Our measurements were between 3% (male) and 6% of the echo based measurements. Differences are likely to reflect a difference in measurement technique (leading edge convention in echo) and differences in cohorts, with risk factors not being excluded in the vast majority of previous studies. When compared to a large non-contrast enhanced gated CT study by Devereaux et al. of 4387 subjects, measuring ascending and descending aortic diameters at the level of the pulmonary artery[9] our results show an aortic diameter that is consistently lower than that recorded in this study (ascending aorta by 42% for both males and females, descending aorta by 18% in males and 15% in females). Possible explanations for this include differences in measurement techniques (outer edge to outer edge used in the CT study versus Inner edge to inner edge in this MR study) and the comparison of differing cohorts. Indeed, comparison with this large CT study is limited given the fact that it enrolled subjects with established cardiovascular risk factors including hypertension (27%), smoking (40%), diabetes (5%) and dyslipidaemia (36%) all which are known to exert independent effects on aortic size and/or function. Aortic root measurements in this study are very similar to those recorded in a recent study by Burman et al.[13]. This is expected given the fact that both utilise SSFP CMR at 1.5 T to measure aortic root diameter in a group of subjects with little or no cardiovascular risk factors (Burman et al. including subjects with systolic blood pressure up to 150 mmHg).

This study is cross-sectional in design and does not examine changes over time related to age and increasing BSA, and is only a comparison of differing cohorts. BMI is a simple measure that is strongly correlated with sophisticated measures of obesity, but can be a misleading measure of obesity in subjects with high levels of muscle mass with normal adipose tissue levels. We are confident that in this sedentary population the elevated BMI values were not driven by elevated muscle mass. To confirm this, on separate analysis, (not shown) increased BMI was directly correlated to increased fat mass not lean mass on bioimpedance analysis, suggesting that the elevated BMI measures seen in this study were driven primarily by fat mass, not lean muscle mass.

Aortic root dimensions were measured in a single longitudinal plane, and further measurements using a second, 'coronal’ LVOT, view or short-axis cross-sectional planes may allow for a more accurate assessment of diameter. Standard long axis planes are routinely acquired in CMR studies however, and would be applicable to widespread clinical practice.

Aortic dimensions were measured at six locations along the aorta. Although five of these positions are in standardised anatomical positions, the abdominal images are acquired at an arbitrary point 12 cm distal to the pulmonary, and not located at an anatomical landmark. Despite this, the location of this slice does allow repeat clinical studies to be performed in subjects.