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Abstract

Aims

In the present study, we assessed correlates and their consistency of ascending aorta (AscAo) measurement in treated hypertensive patients.

Methods and results

A total of 1634 patients ≥ 18 years old with available AscAo ultrasound were included. Ascending aorta was measured at end-diastole with leading edge to leading edge method, perpendicular to the long axis of the aorta in parasternal long-axis view at its maximal identifiable dimension. Correlations of AscAo and AscAo normalized for height (AscAo/HT) or body surface area (AscAo/BSA) with demographics and metabolic profile were explored. Multi-variable regression was also used to identify potential confounders influencing univariate correlations. Sensitivity analysis was performed using cardiovascular (CV) outcome. Correlations with age, estimated glomerular filtration rate, systolic blood pressure (BP), and heart rate (HR) were similar among the three aortic measures. Women exhibited smaller AscAo but larger AscAo/BSA than men with AscAo/HT offsetting the sex difference. Obesity and diabetes were associated with greater AscAo and AscAo/HT but with smaller AscAo/BSA (all P < 0.001). In multi-variable regression model, all aortic measure confirmed the sign of their relations with sex and metabolic profile independently of age, BP, and HR. In Kaplan–Mayer analysis, only dilated AscAo and AscAo/HT were significantly associated with increased risk of CV events (both P < 0.008).

Conclusions

Among patients with long-standing controlled systemic hypertension, magnitude of aortic remodelling is influenced by the type of the measure adopted, with physiological consistency only for AscAo and AscAo/HT, but not for AscAo/BSA.

Lay Summary

Long-standing hypertension leads to the development of aortic remodelling. In particular, the haemodynamic overload due to high blood pressure may contribute to the development of ascending aorta (AscAo) dilatation. With present study we analysed, in treated hypertensive patients, the spectrum of AscAo dilatation using different anthropometric criteria reporting the clinical and echocardiographic correlates:

  • Indexing AscAo for body surface area (BSA) leads to inconsistent negative association with obesity and other metabolic abnormalities while AscAo and AscAo indexed for height present consistent pathophysiologic profile.

  • In sensitivity analysis, AscAo and AscAo indexed for height are significantly associated with incident cardiovascular events while indexation for BSA is not, strongly suggesting the use of AscAo/BSA should be discouraged.

Aortic remodelling, Obesity, Cardiac structure, Cardiovascular risk

See the editorial comment for this article ‘Why should ascending aorta dimension be measured and how should it be normalized in hypertensive patients?’, by N.J. Guettler, https://doi.org/10.1093/eurjpc/zwad255.

Introduction

Arterial hypertension increases aortic wall stress, one of the causes of increase in ascending aorta (AscAo) inner dimension.1–3 In hypertensive patients, the dilatation of AscAo has been associated with increased cardiovascular (CV) risk.4,5 Similar to other CV structural parameters [i.e. left atrium and left ventricular (LV) mass], AscAo dimension is highly correlated to demographic, anthropometric, and clinical factors directly impacting on outcomes.6 Few studies have specifically evaluated prevalence and determinants of AscAo remodelling in patients with treated arterial hypertension.

One specific and very important issue concerns normalization for body size, which is largely adopted. As recently pointed out by the latest American guidelines on aortic disease, different methods of indexation might be used for AscAo, though surgical thresholds are still reported as crude diameter.7 How much indexation of AscAo for body size influences pathophysiological correlates, especially in the context of arterial hypertension, is unknown.

Accordingly, the aims of the present study were (i) to report the spectrum of aortic dilatation among patients with long-standing controlled systemic arterial hypertension using different anthropometric criteria, (ii) to explore clinical and echocardiographic correlates of AscAo, and (iii) to develop sensitivity analysis on the explored measures.

Methods

Patient population

The Campania Salute Network (CSN) Registry is an open electronic registry, networking community hospital-based hypertension clinics and general practitioners from the Campania region in Southern Italy to the Hypertension Research Center of Federico II University Hospital in Naples, (ClinicalTrials.gov Identifier: NCT02211365).8–10 As previously reported in detail, recruited subjects are referred to the Hypertension Research Center for definitive diagnosis and related therapeutic interventions.11 For the present analysis, 1634 hypertensive patients were selected, based on the following inclusion criteria: (i) age ≥ 18 years; (ii) available transthoracic two-dimensional Doppler echocardiogram (TTE) examination including AscAo measurements; (iii) no more than mild valvular disease; (iv) no evidence of bicuspid aortic valve and/or Marfan syndrome. The Federico II University Hospital Ethic Committee approved the database generation of the CSN. All participants signed written informed consent for the possibility of using the data for scientific purposes.

Cardiovascular risk factors assessment

Detailed medical history and clinical examination were performed at the first visit by a dedicated cardiologist.12 Auscultatory or oscillometric semi-automatic sphygmomanometers attended by physicians were used, with cuffs of appropriate size.8 Systolic and diastolic blood pressures (BPs) were measured after 5-min resting in the sitting position, three times at 1-min interval, according current guidelines on hypertension.13 The average of the two last measurements was taken as the office BP (OBP).

Obesity was defined as a body mass index (BMI) ≥ 30 kg/m2. Fasting glucose and lipid profile were measured by standard methods. Diabetes was defined as history of diabetes, the use of any anti-diabetic medication, or presence of fasting blood glucose ≥126 mg/dL confirmed on two different occasions.11 Estimated glomerular filtration rate (eGFR) was estimated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.14

Echocardiography

TTEs were performed using commercially available phased-array machines following a standardized protocol.15,16 Echocardiograms were read offline by one expert reader under the supervision of a senior faculty member, on dedicated workstation as previously reported. Left ventricular hypertrophy (LVH) was identified by prognostically validated sex-specific cut-off values for LV mass index (LVMi)/height (HT): >47 g/m2.7 in women and >50 g/m2.7 in men, respectively.13,17 Left ventricular end-diastolic dimension was ratiometrically normalized for HT.17 Relative wall thickness was calculated as the ratio between posterior wall thickness and LV internal radius at end-diastole and considered increased if ≥0.43.13 Left ventricular systolic function was assessed by LV ejection fraction.15 Based on a two-element Windkessel model of the circulatory system, arterial stiffness was estimated as the ratio of brachial pulse pressure (PP) to stroke index, based on the z-derived method18 and normalized for body HT in meters [stroke volume index (SVi)] raised to the allometric power of 2.04 (PP/SVi).19,20

Ascending aorta was measured, at the time of the first echocardiogram, at end-diastole with leading edge to leading edge method, perpendicular to the long axis of the aorta in parasternal long-axis view at its maximal identifiable dimension (AscAo).21 In addition, AscAo was indexed to patient body surface area (AscAo/BSA) and HT (AscAo/HT).

Outcome

Long-term CV events (i.e. non-fatal stroke or myocardial infarction, sudden cardiac death, heart failure requiring hospitalization, transient ischemic attack, myocardial revascularization, de novo angina, carotid stenting, and atrial fibrillation) were registered through clinical follow-up visits and/or direct contact with patients’ general practitioners.22–24

Statistical analysis

Statistical analysis was performed using IBM SPSS 23 (IBM Corporation, Armonk, NY, USA). For descriptive statistics, categorical variables are presented as percentages, and continuous variables are presented as mean ± standard deviation (SD) or median and interquartile range (IQR) depending on their distribution. Pearson correlation analysis was used to assess main correlates of AscAo, AscAo/BSA, and AscAo/HT. Multi-variable regression models were built using a backward procedure to assess independent correlates of AscAo, AscAo/BSA, and AscAo/HT, including significant variables identified in univariate analysis.

For sensitivity analysis, AscAo was considered dilated if above the 75th percentile of the normal distribution for AscAo, AscAo/BSA, and AscAo/HT. Kaplan–Mayer curves for incident CV events were built according to each measurements of AscAo.

Results

We analysed data from 1634 hypertensive patients (41% women), mean age 53.6 ± 13 years, 8.7% diabetic, 28% obese. Diastolic BP was lower and PP was higher in women than in men (Table 1). In the whole population sample, AscAo measured 33 ± 4.3 mm (IQR 30–36), AscAo/BSA was 17.6 ± 2.7 mm/m2, and AscAo/HT was 19.7 ± 2.6 mm/m. Women exhibited smaller AscAo, a sex difference that was offset by normalization for HT. In contrast, women exhibited larger AscAo/BSA than men.

Table 1
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Characteristics of the study population

VariablesValue (n = 1634)Men (n = 965)Women (n = 669)
Age (years)53.6 ± 1352.1 ± 13*55.7 ± 12.6
Women (%)41——
Obesity (%)2826*31
Diabetes (%)998
Systolic BP (mmHg)142 ± 20142 ± 19.6142.9 ± 22
Diastolic BP (mmHg)86.9 ± 1287.9 ± 12.3*85.5 ± 11.9
Heart rate (b.p.m.)73.6 ± 11.773.4 ± 11.974 ± 11.3
eGFR (mL/min/1.73m2)81.9 ± 17.382.9 ± 16.3*80.4 ± 18.5
Total serum cholesterol (mg/dL)200 ± 39.8196.2 ± 39.4*206.9 ± 39.5
Serum triglycerides (mg/dL)131 ± 66140.1 ± 76.6*121.2 ± 61.1
Pulse pressure (mmHg)55 ± 1654.1 ± 15.5*57.4 ± 18.1
Isolated systolic hypertension (%)1513*19
LV end-diastolic diameter/height (mm/m)2.9 ± 0.22.94 ± 0.22.95 ± 0.2
RWT0.38 ± 0.040.38 ± 0.040.38 ± 0.04
LV mass index (g/m2.7)46 ± 9.346.3 ± 9.445.5 ± 9.1
Stroke index (mL/m2.04)25.7 ± 3.525.4 ± 3.4*26.1 ± 3.1
PP/SVi (mmHg/mL2.04)2.3 ± 0.72.27 ± 0.652.31 ± 0.7
AscAo (mm)33 ± 4.133.9 ± 3.9*31.9 ± 4.1
AscAo/HT (mm/m)19.7 ± 2.519.6 ± 2.419.8 ± 2.6
AscAo/BSA (mm/m2)17.6 ± 2.617.1 ± 2.4*18.2 ± 2.7
VariablesValue (n = 1634)Men (n = 965)Women (n = 669)
Age (years)53.6 ± 1352.1 ± 13*55.7 ± 12.6
Women (%)41——
Obesity (%)2826*31
Diabetes (%)998
Systolic BP (mmHg)142 ± 20142 ± 19.6142.9 ± 22
Diastolic BP (mmHg)86.9 ± 1287.9 ± 12.3*85.5 ± 11.9
Heart rate (b.p.m.)73.6 ± 11.773.4 ± 11.974 ± 11.3
eGFR (mL/min/1.73m2)81.9 ± 17.382.9 ± 16.3*80.4 ± 18.5
Total serum cholesterol (mg/dL)200 ± 39.8196.2 ± 39.4*206.9 ± 39.5
Serum triglycerides (mg/dL)131 ± 66140.1 ± 76.6*121.2 ± 61.1
Pulse pressure (mmHg)55 ± 1654.1 ± 15.5*57.4 ± 18.1
Isolated systolic hypertension (%)1513*19
LV end-diastolic diameter/height (mm/m)2.9 ± 0.22.94 ± 0.22.95 ± 0.2
RWT0.38 ± 0.040.38 ± 0.040.38 ± 0.04
LV mass index (g/m2.7)46 ± 9.346.3 ± 9.445.5 ± 9.1
Stroke index (mL/m2.04)25.7 ± 3.525.4 ± 3.4*26.1 ± 3.1
PP/SVi (mmHg/mL2.04)2.3 ± 0.72.27 ± 0.652.31 ± 0.7
AscAo (mm)33 ± 4.133.9 ± 3.9*31.9 ± 4.1
AscAo/HT (mm/m)19.7 ± 2.519.6 ± 2.419.8 ± 2.6
AscAo/BSA (mm/m2)17.6 ± 2.617.1 ± 2.4*18.2 ± 2.7

AscAO, ascending aorta; BP, blood pressure; LV, left ventricle; PP/SVi, pulse pressure/stroke volume index; RWT, relative wall thickness.

*P < 0.05.

Table 1
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Characteristics of the study population

VariablesValue (n = 1634)Men (n = 965)Women (n = 669)
Age (years)53.6 ± 1352.1 ± 13*55.7 ± 12.6
Women (%)41——
Obesity (%)2826*31
Diabetes (%)998
Systolic BP (mmHg)142 ± 20142 ± 19.6142.9 ± 22
Diastolic BP (mmHg)86.9 ± 1287.9 ± 12.3*85.5 ± 11.9
Heart rate (b.p.m.)73.6 ± 11.773.4 ± 11.974 ± 11.3
eGFR (mL/min/1.73m2)81.9 ± 17.382.9 ± 16.3*80.4 ± 18.5
Total serum cholesterol (mg/dL)200 ± 39.8196.2 ± 39.4*206.9 ± 39.5
Serum triglycerides (mg/dL)131 ± 66140.1 ± 76.6*121.2 ± 61.1
Pulse pressure (mmHg)55 ± 1654.1 ± 15.5*57.4 ± 18.1
Isolated systolic hypertension (%)1513*19
LV end-diastolic diameter/height (mm/m)2.9 ± 0.22.94 ± 0.22.95 ± 0.2
RWT0.38 ± 0.040.38 ± 0.040.38 ± 0.04
LV mass index (g/m2.7)46 ± 9.346.3 ± 9.445.5 ± 9.1
Stroke index (mL/m2.04)25.7 ± 3.525.4 ± 3.4*26.1 ± 3.1
PP/SVi (mmHg/mL2.04)2.3 ± 0.72.27 ± 0.652.31 ± 0.7
AscAo (mm)33 ± 4.133.9 ± 3.9*31.9 ± 4.1
AscAo/HT (mm/m)19.7 ± 2.519.6 ± 2.419.8 ± 2.6
AscAo/BSA (mm/m2)17.6 ± 2.617.1 ± 2.4*18.2 ± 2.7
VariablesValue (n = 1634)Men (n = 965)Women (n = 669)
Age (years)53.6 ± 1352.1 ± 13*55.7 ± 12.6
Women (%)41——
Obesity (%)2826*31
Diabetes (%)998
Systolic BP (mmHg)142 ± 20142 ± 19.6142.9 ± 22
Diastolic BP (mmHg)86.9 ± 1287.9 ± 12.3*85.5 ± 11.9
Heart rate (b.p.m.)73.6 ± 11.773.4 ± 11.974 ± 11.3
eGFR (mL/min/1.73m2)81.9 ± 17.382.9 ± 16.3*80.4 ± 18.5
Total serum cholesterol (mg/dL)200 ± 39.8196.2 ± 39.4*206.9 ± 39.5
Serum triglycerides (mg/dL)131 ± 66140.1 ± 76.6*121.2 ± 61.1
Pulse pressure (mmHg)55 ± 1654.1 ± 15.5*57.4 ± 18.1
Isolated systolic hypertension (%)1513*19
LV end-diastolic diameter/height (mm/m)2.9 ± 0.22.94 ± 0.22.95 ± 0.2
RWT0.38 ± 0.040.38 ± 0.040.38 ± 0.04
LV mass index (g/m2.7)46 ± 9.346.3 ± 9.445.5 ± 9.1
Stroke index (mL/m2.04)25.7 ± 3.525.4 ± 3.4*26.1 ± 3.1
PP/SVi (mmHg/mL2.04)2.3 ± 0.72.27 ± 0.652.31 ± 0.7
AscAo (mm)33 ± 4.133.9 ± 3.9*31.9 ± 4.1
AscAo/HT (mm/m)19.7 ± 2.519.6 ± 2.419.8 ± 2.6
AscAo/BSA (mm/m2)17.6 ± 2.617.1 ± 2.4*18.2 ± 2.7

AscAO, ascending aorta; BP, blood pressure; LV, left ventricle; PP/SVi, pulse pressure/stroke volume index; RWT, relative wall thickness.

*P < 0.05.

Ascending aorta dimension and clinical and echocardiographic correlates

Table 2 displays a correlation matrix for AscAo, AscAo/BSA, and AscAo/HT. Correlations with age, eGFR, systolic BP, and heart rate (HR) were similar among the three aortic measurements.

Table 2
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Correlation coefficients for ascending aorta, ascending/body surface area, and ascending aorta/height

VariablesAscAoAscAo/BSAAscAo/HT
Age (years)0.33***0.449***0.447***
Sex (m/f)−0.249***0.206***0.038
Obesity (n/y)0.086***−0.234***0.103***
Diabetes (n/y)0.068**0.0320.081***
eGFR (mL/min/1.73 m2)−0.228***−0.289***−0.289***
Total cholesterol (mg/dL)−0.52−0.004−0.017
Triglycerides (mg/dL)0.079***−0.050.05*
Systolic BP (mmHg)0.066**0.065*0.085**
Diastolic BP (mmHg)0.075**−0.0380.028
Pulse pressure (mmHg)0.0330.111***0.089**
Heart rate (b.p.m.)−0.120***−0.103***−0.107***
Duration of hypertension (years)0.211***0.195***0.255***
VariablesAscAoAscAo/BSAAscAo/HT
Age (years)0.33***0.449***0.447***
Sex (m/f)−0.249***0.206***0.038
Obesity (n/y)0.086***−0.234***0.103***
Diabetes (n/y)0.068**0.0320.081***
eGFR (mL/min/1.73 m2)−0.228***−0.289***−0.289***
Total cholesterol (mg/dL)−0.52−0.004−0.017
Triglycerides (mg/dL)0.079***−0.050.05*
Systolic BP (mmHg)0.066**0.065*0.085**
Diastolic BP (mmHg)0.075**−0.0380.028
Pulse pressure (mmHg)0.0330.111***0.089**
Heart rate (b.p.m.)−0.120***−0.103***−0.107***
Duration of hypertension (years)0.211***0.195***0.255***

AscAo, ascending aorta; BP, blood pressure; BSA, body surface area; HT, height; eGFR, estimated glomerular filtration rate.

*P < 0.05, **P < 0.01, ***P < 0.001.

Table 2
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Correlation coefficients for ascending aorta, ascending/body surface area, and ascending aorta/height

VariablesAscAoAscAo/BSAAscAo/HT
Age (years)0.33***0.449***0.447***
Sex (m/f)−0.249***0.206***0.038
Obesity (n/y)0.086***−0.234***0.103***
Diabetes (n/y)0.068**0.0320.081***
eGFR (mL/min/1.73 m2)−0.228***−0.289***−0.289***
Total cholesterol (mg/dL)−0.52−0.004−0.017
Triglycerides (mg/dL)0.079***−0.050.05*
Systolic BP (mmHg)0.066**0.065*0.085**
Diastolic BP (mmHg)0.075**−0.0380.028
Pulse pressure (mmHg)0.0330.111***0.089**
Heart rate (b.p.m.)−0.120***−0.103***−0.107***
Duration of hypertension (years)0.211***0.195***0.255***
VariablesAscAoAscAo/BSAAscAo/HT
Age (years)0.33***0.449***0.447***
Sex (m/f)−0.249***0.206***0.038
Obesity (n/y)0.086***−0.234***0.103***
Diabetes (n/y)0.068**0.0320.081***
eGFR (mL/min/1.73 m2)−0.228***−0.289***−0.289***
Total cholesterol (mg/dL)−0.52−0.004−0.017
Triglycerides (mg/dL)0.079***−0.050.05*
Systolic BP (mmHg)0.066**0.065*0.085**
Diastolic BP (mmHg)0.075**−0.0380.028
Pulse pressure (mmHg)0.0330.111***0.089**
Heart rate (b.p.m.)−0.120***−0.103***−0.107***
Duration of hypertension (years)0.211***0.195***0.255***

AscAo, ascending aorta; BP, blood pressure; BSA, body surface area; HT, height; eGFR, estimated glomerular filtration rate.

*P < 0.05, **P < 0.01, ***P < 0.001.

Obesity was associated with greater AscAo and AscAo/HT but with lower AscAo/BSA. Similarly, diabetes and triglycerides were associated with greater aortic AscAo and AscAo/HT but lower AscAo/BSA. All three aortic measures weakly correlated with systolic BP, whereas the correlation was not significant for diastolic BP when normalized for body size. Estimated glomerular filtration rate, HR, and duration of hypertension were also correlated with all three measures of AscAo (Table 2).

Ascending aorta was better correlated with AscAo/HT than with AscAo/BSA (0.98 and 0.69, respectively, both P < 0.0001). Table 3 displays that AscAo correlated positively with LV end-diastolic dimension, LV mass, and stroke volume (all P < 0.01). Ascending aorta/BSA and AscAo/HT were positively associated with LV end-diastolic dimension index, LVMi, and SVi.

Table 3
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Pearson’s correlation coefficient for ascending aorta, ascending/body surface area, and ascending aorta/height

VariablesAscAoAscAo/BSAAscAo/HT
LV end-diastolic diameter (mm)0.352***——
LV end-diastolic diameter/height (mm/m)—0.232***0.348***
RWT0.0240.0220.062*
LV mass (g)0.450***——
Stroke volume (mL)0.250***——
LV mass index (g/m2.7)—0.270***0.450***
Stroke index (mL/m2.04)—0.202***0.267***
PP/SVi (mmHg/mL2.04)—0.0080.085
VariablesAscAoAscAo/BSAAscAo/HT
LV end-diastolic diameter (mm)0.352***——
LV end-diastolic diameter/height (mm/m)—0.232***0.348***
RWT0.0240.0220.062*
LV mass (g)0.450***——
Stroke volume (mL)0.250***——
LV mass index (g/m2.7)—0.270***0.450***
Stroke index (mL/m2.04)—0.202***0.267***
PP/SVi (mmHg/mL2.04)—0.0080.085

AscAo, ascending aorta; BSA, body surface area; HT, height; LV, left ventricle; PP/SVi, pulse pressure/stroke volume index; RWT, relative wall thickness.

*P < 0.05, **P < 0.01, ***P < 0.001.

Table 3
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Pearson’s correlation coefficient for ascending aorta, ascending/body surface area, and ascending aorta/height

VariablesAscAoAscAo/BSAAscAo/HT
LV end-diastolic diameter (mm)0.352***——
LV end-diastolic diameter/height (mm/m)—0.232***0.348***
RWT0.0240.0220.062*
LV mass (g)0.450***——
Stroke volume (mL)0.250***——
LV mass index (g/m2.7)—0.270***0.450***
Stroke index (mL/m2.04)—0.202***0.267***
PP/SVi (mmHg/mL2.04)—0.0080.085
VariablesAscAoAscAo/BSAAscAo/HT
LV end-diastolic diameter (mm)0.352***——
LV end-diastolic diameter/height (mm/m)—0.232***0.348***
RWT0.0240.0220.062*
LV mass (g)0.450***——
Stroke volume (mL)0.250***——
LV mass index (g/m2.7)—0.270***0.450***
Stroke index (mL/m2.04)—0.202***0.267***
PP/SVi (mmHg/mL2.04)—0.0080.085

AscAo, ascending aorta; BSA, body surface area; HT, height; LV, left ventricle; PP/SVi, pulse pressure/stroke volume index; RWT, relative wall thickness.

*P < 0.05, **P < 0.01, ***P < 0.001.

In multiple linear regression analysis, both AscAo and AscAo/HT were significantly and independently associated with older age, lower systolic BP, and higher diastolic BP. In contrast, larger AscAo/BSA was found in normal weight than in obese individuals (Table 4).

Table 4
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Multi-variable regression model for main determinants of ascending aorta, ascending/body surface area, and ascending aorta/height

Dependent variableStandardized coefficientsP
AscAo (R2 = 0.30)
Age (years)0.2950.0001
Sex (men/women)−0.100.001
Systolic BP (mmHg)−0.1330.002
Diastolic BP (mmHg)0.2010.0001
Duration of hypertension (years)0.0520.06
Heart rate (b.p.m.)−0.050.07
Obesity (n/y)0.0160.535
Triglycerides (mg/dL)−0.0020.993
Diabetes (n/y)−0.0410.097
eGFR (mL/min/1.73m2)−0.0430.156
LV mass (g)0.3260.0001
Stroke volume (mL)0.0020.959
AscAo/HT (R2 = 0.33)
Age (years)0.3570.0001
Sex (men/women)0.0380.131
Systolic BP (mmHg)−0.1220.0001
Diastolic BP (mmHg)0.1950.0001
Heart rate (b.p.m.)−0.0340.177
Duration of hypertension (years)0.0450.098
Obesity (n/y)0.0080.760
Triglycerides (mg/dL)0.010.697
Diabetes (n/y)−0.0390.115
eGFR (mL/min/1.73 m2)−0.040.143
LV mass index (g/m2.7)0.2910.001
Stroke volume index (mL/m2.04)0.0170.590
AscAo/BSA (R2 = 0.35)
Age (years)0.3560.0001
Sex (men/women)0.1910.0001
Systolic BP (mmHg)−0.0650.038
Diastolic BP (mmHg)0.1350.0001
Heart rate (b.p.m.)−0.0310.214
Duration of hypertension (years)0.0160.556
Obesity (n/y)−0.3010.0001
Triglycerides (mg/dL)−0.0120.615
Diabetes (n/y)−0.0470.054
eGFR (mL/min/1.73 m2)−0.0530.069
LV mass index (g/m2.7)0.2000.0001
Stroke volume index (mL/m2.04)0.0470.122
Dependent variableStandardized coefficientsP
AscAo (R2 = 0.30)
Age (years)0.2950.0001
Sex (men/women)−0.100.001
Systolic BP (mmHg)−0.1330.002
Diastolic BP (mmHg)0.2010.0001
Duration of hypertension (years)0.0520.06
Heart rate (b.p.m.)−0.050.07
Obesity (n/y)0.0160.535
Triglycerides (mg/dL)−0.0020.993
Diabetes (n/y)−0.0410.097
eGFR (mL/min/1.73m2)−0.0430.156
LV mass (g)0.3260.0001
Stroke volume (mL)0.0020.959
AscAo/HT (R2 = 0.33)
Age (years)0.3570.0001
Sex (men/women)0.0380.131
Systolic BP (mmHg)−0.1220.0001
Diastolic BP (mmHg)0.1950.0001
Heart rate (b.p.m.)−0.0340.177
Duration of hypertension (years)0.0450.098
Obesity (n/y)0.0080.760
Triglycerides (mg/dL)0.010.697
Diabetes (n/y)−0.0390.115
eGFR (mL/min/1.73 m2)−0.040.143
LV mass index (g/m2.7)0.2910.001
Stroke volume index (mL/m2.04)0.0170.590
AscAo/BSA (R2 = 0.35)
Age (years)0.3560.0001
Sex (men/women)0.1910.0001
Systolic BP (mmHg)−0.0650.038
Diastolic BP (mmHg)0.1350.0001
Heart rate (b.p.m.)−0.0310.214
Duration of hypertension (years)0.0160.556
Obesity (n/y)−0.3010.0001
Triglycerides (mg/dL)−0.0120.615
Diabetes (n/y)−0.0470.054
eGFR (mL/min/1.73 m2)−0.0530.069
LV mass index (g/m2.7)0.2000.0001
Stroke volume index (mL/m2.04)0.0470.122

AscAo, ascending aorta; BP, blood pressure; eGFR, estimated glomerular filtration rate; LV, left ventricle.

Table 4
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Multi-variable regression model for main determinants of ascending aorta, ascending/body surface area, and ascending aorta/height

Dependent variableStandardized coefficientsP
AscAo (R2 = 0.30)
Age (years)0.2950.0001
Sex (men/women)−0.100.001
Systolic BP (mmHg)−0.1330.002
Diastolic BP (mmHg)0.2010.0001
Duration of hypertension (years)0.0520.06
Heart rate (b.p.m.)−0.050.07
Obesity (n/y)0.0160.535
Triglycerides (mg/dL)−0.0020.993
Diabetes (n/y)−0.0410.097
eGFR (mL/min/1.73m2)−0.0430.156
LV mass (g)0.3260.0001
Stroke volume (mL)0.0020.959
AscAo/HT (R2 = 0.33)
Age (years)0.3570.0001
Sex (men/women)0.0380.131
Systolic BP (mmHg)−0.1220.0001
Diastolic BP (mmHg)0.1950.0001
Heart rate (b.p.m.)−0.0340.177
Duration of hypertension (years)0.0450.098
Obesity (n/y)0.0080.760
Triglycerides (mg/dL)0.010.697
Diabetes (n/y)−0.0390.115
eGFR (mL/min/1.73 m2)−0.040.143
LV mass index (g/m2.7)0.2910.001
Stroke volume index (mL/m2.04)0.0170.590
AscAo/BSA (R2 = 0.35)
Age (years)0.3560.0001
Sex (men/women)0.1910.0001
Systolic BP (mmHg)−0.0650.038
Diastolic BP (mmHg)0.1350.0001
Heart rate (b.p.m.)−0.0310.214
Duration of hypertension (years)0.0160.556
Obesity (n/y)−0.3010.0001
Triglycerides (mg/dL)−0.0120.615
Diabetes (n/y)−0.0470.054
eGFR (mL/min/1.73 m2)−0.0530.069
LV mass index (g/m2.7)0.2000.0001
Stroke volume index (mL/m2.04)0.0470.122
Dependent variableStandardized coefficientsP
AscAo (R2 = 0.30)
Age (years)0.2950.0001
Sex (men/women)−0.100.001
Systolic BP (mmHg)−0.1330.002
Diastolic BP (mmHg)0.2010.0001
Duration of hypertension (years)0.0520.06
Heart rate (b.p.m.)−0.050.07
Obesity (n/y)0.0160.535
Triglycerides (mg/dL)−0.0020.993
Diabetes (n/y)−0.0410.097
eGFR (mL/min/1.73m2)−0.0430.156
LV mass (g)0.3260.0001
Stroke volume (mL)0.0020.959
AscAo/HT (R2 = 0.33)
Age (years)0.3570.0001
Sex (men/women)0.0380.131
Systolic BP (mmHg)−0.1220.0001
Diastolic BP (mmHg)0.1950.0001
Heart rate (b.p.m.)−0.0340.177
Duration of hypertension (years)0.0450.098
Obesity (n/y)0.0080.760
Triglycerides (mg/dL)0.010.697
Diabetes (n/y)−0.0390.115
eGFR (mL/min/1.73 m2)−0.040.143
LV mass index (g/m2.7)0.2910.001
Stroke volume index (mL/m2.04)0.0170.590
AscAo/BSA (R2 = 0.35)
Age (years)0.3560.0001
Sex (men/women)0.1910.0001
Systolic BP (mmHg)−0.0650.038
Diastolic BP (mmHg)0.1350.0001
Heart rate (b.p.m.)−0.0310.214
Duration of hypertension (years)0.0160.556
Obesity (n/y)−0.3010.0001
Triglycerides (mg/dL)−0.0120.615
Diabetes (n/y)−0.0470.054
eGFR (mL/min/1.73 m2)−0.0530.069
LV mass index (g/m2.7)0.2000.0001
Stroke volume index (mL/m2.04)0.0470.122

AscAo, ascending aorta; BP, blood pressure; eGFR, estimated glomerular filtration rate; LV, left ventricle.

Table 4 also shows that AscAo was larger in men, even independently of other correlates, a sex difference that disappeared when AscAo was normalized for HT. In contrast, AscAo/BSA was confirmed to be greater in women also independently of confounders.

Regardless of the use of any type of normalization, greater AscAo was associated with greater LV mass and LVMi (Table 4).

Sensitivity analysis: ascending aorta dimension and clinical outcomes

To clarify inconsistencies among the different measures of AscAo (raw and normalized values), especially concerning the normalization for BSA, available information on patients’ clinical outcomes during follow-up was used for a sensitivity analysis, to check the ability of AscAo, AscAo/HT, and AscAo/BSA to predict CV events, using Kaplan–Mayer plots and log-rank analysis.

Ascending aorta was considered dilated, based on the 75th percentile of the normal distribution of each of the three measurements, as seen in Figure 1. Accordingly, AscAo was considered dilated if >36 mm, AscAo/HT if >21.2 mm/m, and AscAo/BSA if >19.1 mm/m2. During a mean follow-up of 18 ± 29 months (IQR 5–35), 23 CV events were adjudicated (including 7 ischaemic strokes, 8 acute coronary syndromes, and 8 atrial fibrillations). As displayed in Figure 2, dilated AscAo and AscAo/HT were associated with increased rate of CV events (P = 0.004 and P = 0.008, respectively) while the association was substantially weaker for dilated AscAo/BSA (P = 0.058).

Normal distribution and selection of highest quartile for ascending aorta, ascending aorta/height, and ascending/body surface area. AscAo, ascending aorta; BSA, body surface area; HT, height; SD, standard deviation.
Figure 1

Normal distribution and selection of highest quartile for ascending aorta, ascending aorta/height, and ascending/body surface area. AscAo, ascending aorta; BSA, body surface area; HT, height; SD, standard deviation.

Open in new tabDownload slide
Kaplan–Mayer analysis for incident cardiovascular events for ascending aorta, ascending aorta/height, and ascending/body surface area. AscAo, ascending aorta; BSA, body surface area; CV, cardiovascular; HT, height; SD, standard deviation.
Figure 2

Kaplan–Mayer analysis for incident cardiovascular events for ascending aorta, ascending aorta/height, and ascending/body surface area. AscAo, ascending aorta; BSA, body surface area; CV, cardiovascular; HT, height; SD, standard deviation.

Open in new tabDownload slide

Discussion

Recent evidence suggests that hypertension can induce aortic remodelling.4,25,26 Thus, correct assessment of AscAo dimension may help select hypertensive patients with hypertension-mediated organ damage (HMOD) and specifically at higher risk of aortic events and help monitor optimal BP targets.7 Previous data from population-based studies have demonstrated that AscAo dilatation is strongly influenced by age, sex, and BP.27,28 Our results are consistent with these previous reports but open a relevant question about the way measurements may be used in clinical practice. Our study evaluates many pathophysiological correlates of AscAo in a population of treated hypertensive patients with the goal of defining the most convenient way to use AscAo measures, comparing physiological correlation of raw values and values normalized for body size, by the most common anthropometric measures, BSA and HT. As seen, the results of the correlation analysis are not consistent for all three measures, indicating that the use of one or another of them is not indifferent in terms of understanding the impact of AscAo dimension on patient profiling.

While the same direction of correlation was found for age (positive), eGFR, HR (both negative), and duration of hypertension (positive) for all three measures we used, different signs were observed for sex and metabolic risk profile. Specifically, AscAo was larger in men than that in women, a sex difference that was reversed when using AscAo/BSA and offset with AscAo/Ht. Such a difference was even more confusing when considering metabolic profile.

Not surprisingly, greater values of AscAo and AscAo/HT were consistently correlated with obesity, diabetes, and higher triglycerides. In contrast, AscAo/BSA was not correlated with diabetes and triglycerides and greater values were found in non-obese patients. In general, AscAo/HT exhibited the same correlation sign as AscAo, while AscAo/BSA went to the opposite direction.

As for other anatomic and functional measures, this apparently paradoxical effect of BSA normalization is due to the presence of body weight in the BSA calculation, which does not take into consideration the alteration of body composition occurring in obesity (increased ratio between fat and lean body mass).

From a clinical point of view, our study strongly suggests to use indexation for HT in the echocardiographic assessment of AscAo in hypertensive patients, avoiding indexation for BSA especially in patients with concomitant obesity and diabetes.

In this regard, a recent guideline of the British Society of Echocardiography recommends aortic measurements normalized for HT, which signals a change from the currently accepted practice of indexing for BSA, as it will have potential benefits especially in overweight–obese individuals with similar reference limits for younger and older individuals.29 In addition, also the 2022 American College of Cardiology/American Heart Association (ACC/AHA) Guideline for the Diagnosis and Management of Aortic Disease7 suggests the use of HT as a method for the correct assessment of aortic dimension.

Our findings add evidence that the use of BSA as the anthropometric parameter to normalize structural component of the CV system can produce misleading information and classification,30 especially in the presence of obesity,30,31 a condition very frequent in the setting of arterial hypertension, and should be definitively discouraged.

Our sensitivity analysis eventually demonstrates that dilated AscAo and AscAo/HT are substantially better markers for increased risk of incident CV events than dilated AscAo/BSA. Also, this analysis extends to the general hypertensive population the evidence that normalization of AscAo for BSA has been demonstrated to underestimate CV risk in patients with thoracic aneurysms when concomitant obesity is present.32

There are two possible causes of the inconsistent pathophysiology found for AscAo/BSA. Firstly, using ratiometric indexation of two geometrically different measures (i.e. AscAo is linear and BSA is quadratic) is mathematically incorrect, because the ratio cannot be linear. Accordingly, to make linear the relation between AscAo and BSA and to use ratiometric criteria for normalization, the BSA square root should be used.33 Secondly, and perhaps even more important, the capacitance and resistance of the arterial tree are strongly interacting with the amount of blood delivered to periphery, which is, in turn, a function of lean body mass, not fat mass.34 In mammals, skeleton length or HT is a strong proxy of the proportionate amount of non-fat body mass35; thus, ratiometric indexation for HT (consistent with the geometric proportions of both variables) helps identify the abnormal deviations associated with abnormal body composition. Furthermore the use body weight in the calculation of BSA, reduce the extent of deviations of AscAo from normality.

Regardless of indexation used, AscAo exhibits a strong correlation with LVMi, suggesting that AscAo is part of the injured CV system and should be considered as another markers of hypertension-mediated target organ damage. For this reason, its assessment should conveniently complete the information provided by the echocardiogram in hypertensive patients,6 without substantially aggravating the workload required for quantitative echocardiography.

Eventually, our study confirms previous findings on the impact of diastolic BP on aortic remodelling demonstrating the effect of distending pressure stretching the aortic wall when the aortic valve is closed.36 Thus, diastolic BP might be considered a determinant of AscAo dilatation, and hypertensive persons with uncontrolled diastolic BP should be considered at risk of aortic dilatation including aortic root and AscAo. Differently from what was demonstrated for the aortic root, stroke volume does not directly affect AscAo. This might be explained by the greater compliance of the Valsalva sinuses compared with the AscAo, the barrage provided by the aortic ridge, and the prevalently longitudinal disposition of elastic fibres in the AscAo downstream of aortic ridge absorbing part of systolic LV stroke.37–39

All the linear models, also including age and gender, barely explained around one-third of the total variance of AscAo dimensions, as revealed by the adjusted coefficients of determination (between 0.30 and 0.35). Therefore, there is wide biological variability in AscAo dimensions not explained by selected variables. In this regard, it should be noted similar values of R2 have also been reported in previous studies on AscAo and aortic root dimension.36,40,41 In our study, multiple linear regression analysis models were run mainly to verify whether the differences found in univariate correlation analysis could be due to the effects of confounders, not really to explore the effect of a comprehensive model on variance of measures of AscAo.

Strengths and limitations

The population sample size used in our study is the highest analysed in recent studies on AscAo.1–5 Furthermore, we specifically included treated hypertensive patients who are more prone to the development of AscAo remodelling as previously reported. The prevalence of obesity is particularly high compared with previous studies allowing our results to give important insights in the management of obese hypertensive patients. As limitation of our study, we should mention that the CSN is an observational registry that can be influenced by bias, a limitation that is difficult to eliminate despite the extensive multi-variable adjustment that we performed. However, we paid particular attention to minimizing both selection and observational bias applying substantially the same protocol to everyone. We routinely performed measurement of AscAo in the parasternal long-axis view at its maximal identifiable diameter, also using non-standard windows with medial and higher intercostal space movement. However, we cannot exclude that in some patients, we might not visualized the region of maximal dilation underestimating the AscAo. Finally, due to the low number of incident CV events, current longitudinal findings need to be considered only in the context of the sensitivity analysis and should be confirmed in larger study populations.

Conclusions

Among patients with long-standing controlled systemic arterial hypertension magnitude of AscAo remodelling and pathophysiologic meanings are influenced by the type of indexation used. AscAo/BSA is negatively associated with obesity and other metabolic abnormalities and only very marginally to incident CV events. In contrast, AscAo and AscAo/HT present consistent pathophysiologic profile and are significantly associated with incident CV events. We conclude that the use of AscAo/BSA should be discouraged. Given the association with age, BP, and markers of HMOD, further studies are needed to better understand the impact of optimal BP control over time in the development of AscAo remodelling.

Author contributions

C.M. and M.V.M. analysed data and drafted the manuscript; M.L., I.F., and C.B. contribute to analyse the data and prepared figures and tables; L.B., C.M., N.D.L., E.D., G.d.S., and G.E. critically revised the paper; and B.T. and R.I. provided data and revised the paper. All authors approved the finale version of the paper.

Funding

Luca Bardi is supported by a research grant from CardioPath PhD program.

Data availability

All data described in the manuscript are available from the corresponding author upon reasonable request.

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Author notes

Conflict of interest: None declared.

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Full Research Paper > Risk Prediction/Assessment & Stratification
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