Late systemic hypertension and aortic arch geometry after successful repair of coarctation of the aorta

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1 European Heart Journal (2004) 25, Clinical research Late systemic hypertension and aortic arch geometry after successful repair of coarctation of the aorta Phalla Ou a,c, Damien Bonnet a,b, *, Louis Auriacombe a, Elisa Pedroni a, Fanny Balleux c, Daniel Sidi a, Elie Mousseaux c,d a Cardiologie Pédiatrique, Department of Pediatrics, Hôpital Necker-Enfants Malades, AP-HP, 149, rue de Sevres, Paris, France b INSERM E0016, Faculté de Médecine Necker-Enfants Malades, Paris, France c INSERM U494, Faculté de Médecine Pitié Salpétrière, Paris, France d Service de Radiologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France Received 27 January 2004; revised 8 July 2004; accepted 15 July 2004 Available online 16 September 2004 KEYWORDS Coarctation; Aortic arch geometry; Magnetic resonance imaging; Hypertension Aims To investigate the role of the geometry of the aortic arch in resting hypertension after successful repair of coarctation (CoA). Methods and results 105 patients (15.3 ± 6 years) with successful repair of aortic CoA underwent blood pressure (BP) measurements at rest and magnetic resonance imaging (MRI) of the aortic arch and left ventricle. Three categories of aortic arch shape were defined based on the global geometry of the aortic arch: gothic, crenel and normal. The ratio of the maximum height/transverse diameter of the aortic arch (A/T), the percentage of residual stenosis (RS), the growth index of the aortic arch segments (GIA), and the left ventricular mass index (LVMI) were calculated. Twenty-seven (25.7%) patients had hypertension (HT). HT was more frequent in patients with gothic arch geometry (20/44, 45.5%) than in crenel geometry (5/18, 27.8%) and in normal geometry (2/43, 4.6%) (P < 0.001). Resting systolic BP and LVMI were significantly higher with gothic arch geometry. In multivariate analysis, the only correlates to HT, to level of systolic BP or to LVMI were A/T and gothic arch geometry. Conclusion Gothic geometry of the aortic arch is associated with resting hypertension in patients having undergone successful repair of CoA. This raises concern about methods to harmoniously repair CoA in order to prevent or delay rest hypertension in adulthood. c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. Introduction Systemic hypertension is a major long-term complication after coarctation (CoA) repair in infancy, as about one * Corresponding author. Tel.: ; fax: address: damien.bonnet@nck.ap-hop-paris.fr (D. Bonnet). third of the patients develop late hypertension at rest. 1 6 Although functional abnormalities have been found in patients with an apparently successful repair of coarctation, the pathophysiology of hypertension in this condition is not fully understood. 5,7 12 Anatomical abnormalities of the aortic arch geometry after CoA repair in patients without recoarctation and/or aortic X/$ - see front matter c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. doi: /j.ehj

2 1854 P. Ou et al. arch hypoplasia have not yet been described. We have sought to determine if the aortic arch geometry visualized by Magnetic Resonance Imaging (MRI) could contribute to hypertension in patients with an apparently successful repair of the CoA. Methods Patients We included in our study 105 consecutive patients who were currently followed in our department after successful CoA repair. Clinical and echocardiographic evidence of successful repair was defined as normal femoral pulses, right arm-leg systolic blood pressure gradient at rest <15 mmhg, and systolic peak flow velocity <3 m/s without diastolic flow in the descending aorta. All patients were in NYHA I. Patients who had CoA associated with complex congenital heart defect were excluded (transposition of the great arteries, congenitally corrected transposition of the great arteries, interrupted aortic arch), as well as all patients who had single ventricle physiology or an aberrant right subclavian artery. Demographic characteristics of the patients are summarized in Table 1. This study was approved by the hospital ethics committee, and all patients or their tutor gave informed written consent. Blood pressure measurements Resting blood pressure (BP) in the right arm and leg was measured simultaneously by an automatic oscillometric device (Accutor 4, Datascope Corp., Montvale, NJ, USA) following at least 10 min of rest in the supine position. The mean of at least three measures of systolic BP, diastolic BP, pulse pressure (PP), and arm-leg systolic BP gradient were used. Hypertension was defined in adults as systolic BP P140 mmhg and/or diastolic BP P90 mmhg, and in children as systolic and/or diastolic BP at rest above the 95 th percentile for sex and age. 13 Group HT included patients with hypertension at rest and group N, those who had a normal BP at rest. MRI measurements All imaging was performed on a 1.5 T magnet with 23 mt/m gradients (Signa LX; GE Medical Systems, Milwaukee, WI, USA). After acquisition of axial images of the thorax, long and short axis image series of the heart were obtained using an ECG-gated 3D FIESTA pulse sequence completed during no more than 24 heart beats within a single breath-hold. A series of T1-weighted images were then obtained using acquisition of a 3D breath-hold Gadolinium-enhanced MR angiography in an oblique sagittal plane to obtain images along the long axis of both the ascending and descending aorta parallel to blood flow (TR/TE = 4.5/2 ms; image matrix size from 128 to ; FOV of mm and 1 3 mm for slice thickness). A total of 0.1 mmol/kg of Gadolinium-DOTA was administered during the acquisition using an automatic power injector at 1.2 ml/s immediately flushed with 20 ml of saline. Analyses of the geometrical parameters of the aortic arch as well as measurements of left ventricular mass were prospectively performed by an experienced observer who was unaware of the BP measurements taken at rest. Aortic arch geometry was assessed using either native or maximal intensity projection images of the thoracic aorta. Aortic diameters were estimated along the ascending aorta (ØA), horizontal aorta (ØH), isthmus (ØI), minimal diameter (Øm), and descending aorta 10 cm distal to the anastomosis (ØD) (Fig. 1). The percentage of residual stenosis (RS) was calculated as 100 [1 (Øm/ØD)]. 14 Growth index of the aortic arch (GIA) defined as [(ØH + ØHI + Øm)/3]/ØA was calculated to assess the development of the horizontal aorta (Fig. 1). Morphology of the aortic arch was assessed in left anterior oblique projection. Three categories of aortic arch shape were defined based on the global geometry of the aortic arch: gothic, crenel and normal (Fig. 2). Gothic arch was characterized by an acute angulation between ascending and descending aorta with the horizontal part of the aorta being either shortened or absent. Crenel arch was characterized by a Table 1 Population characteristics Mean ± SD Median (Range) Demography n 105 M/F 67/38 Age (years) 15.3 ± (6 34) Anthropometry Weight (kg) 47 ± (16 80) Height (cm) ± ( ) Blood pressure at rest (upper right limb) Systolic BP (mmhg) ± (80 159) Diastolic BP (mmhg) 61.9 ± (38 88) Pulse pressure (mmhg) 60.5 ± (23 98) Surgery Age at operation (months) 22.1 ± ( ) Follow-up since surgery (years) 13.7 ± (1 33) Type of surgery End to end anastomosis 94 Subclavian flap aortoplasty 11

3 Late systemic hypertension and aortic arch geometry after successful repair of coarctation of the aorta 1855 Fig. 1 On the left: transverse diameter of the aortic arch (T) was defined as the maximal horizontal distance between the midpoints of the ascending and descending aorta, close to the axial plane going through the right pulmonary artery. Height of the aortic arch (A) was defined as the maximal vertical distance between T and the highest mid-point of the aortic arch. On the right: estimation of the aortic diameters along the ascending aorta (ØA), horizontal aorta (ØH), minimal diameter (Øm), isthmus (ØI), and descending aorta 10 cm distal to the anastomosis (ØD). Fig. 2 Three different morphologies of the aortic arch after coarctation repair (top). From left to right: gothic geometry, crenel form and normal form (see definitions in the text). At the bottom, percentage of patients with normal blood pressure (N in white) and hypertension (HT in black) in the 3 types of aortic arch geometry.

4 1856 P. Ou et al. Table 2 Clinical and geometric variables in the 3 subtypes of aortic arch geometry Gothic Crenel Normal P value Global P Gothic/ Normal Gothic/ Crenel Crenel/ Normal n (total = 105) Age (years) 18.4 ± ± ± Weight (kg) 52.8 ± ± ± Height (cm) ± ± ± Follow-up since surgery (years) 15.1 ± ± ± Systolic BP (mmhg) ± ± ± < Diastolic BP (mmhg) 60.9 ± ± ± Pulse pressure (mmhg) 69 ± ± ± 13.4 < < Arm-leg systolic BP gradient (mmhg) 7.2 ± ± ± Heart rate (bpm) 99.6 ± ± ± A/T 0.83 ± ± ± 0.13 < < Residual stenosis (%) 21.1 ± ± ± Aortic arch growth index 0.7 ± ± ± Left ventricular mass index (g/m 2 ) 92.4 ± ± ± rectangular form of the aortic arch with a normal length of the horizontal aorta. Transversal diameter of the aortic arch (T) was defined as the maximal horizontal distance between the midpoints of the ascending and descending aorta, close to the axial plane going through the right pulmonary artery. Height of the aortic arch (A) was defined as the maximal vertical distance between T and the highest midpoint of the aortic arch. The ratio A/T was also calculated (Fig. 1). Using the single short axis view at the level between the basal third and the mid-ventricular third of the left ventricle, mean thickness of the left ventricle and the diameter of the cavity were estimated after determination of endocardial and epicardial borders. As previously described using echocardiography, a geometric formula was then applied to estimate the left ventricular mass index (LVMI). 15 Statistical analysis All data were stored and analysed using the StatView SE software and the R software Version The normality Kolmogorov Smirnov test was performed to determine whether continuous variables were normally distributed. Data are presented as the mean value ±SD, ranges and median when appropriate. Univariate comparisons of continuous variables between HT and N groups were performed by using the Student t test or the Wilcoxon s rank-sum test when the normality assumption was not satisfied. Categorical variables were compared by using the v 2 test. Multivariate analyses were used to determine prognostic factors for hypertension at rest (HT or N status), for the level of resting systolic BP as well as for LVMI. The variables used were age at operation, age at time of the study, height, weight, arm-leg systolic BP gradient, A/T and aortic arch geometry category (gothic, crenel, normal). First, we studied the level of systolic BP or LVMI as the response variable, using multiple linear regression or analyses of covariance when appropriate. The linearity assumption was assessed graphically for the continuous independent variables. We checked before normality and homogeneity of variance of the residuals with plots of residuals against fitted value and histograms. When multiple comparisons were performed, we used the Tukey method to compute the adjusted P-value. Secondly, we studied hypertensive status (HT or N) as a response variable, using multiple logistic regression analysis models. Goodness-of-fit of these models were checked by using the Le Cessie-van Houwelingen-Copas-Hosmer test. When multiple comparisons were performed, we used the Bonferronis method to compute the adjusted P-value. A two sided P-value of 0.05 or less was considered to be statistically significant. Results Aortic arch geometry Forty-four (42%) patients had the gothic geometry, 18 (17%) had the crenel geometry, and 43 (41%) had the normal geometry. As anticipated, A/T was significantly higher in patients with a gothic geometry (A/T = l0.83 ± 0,14) when compared to the two other morphologies (P < ). There were no differences among the three geometries in any of the other dimensions of the aortic arch, in particular, those of residual stenosis and of aortic arch growth index (Table 2). There was no correlation between A/T and age, RS or GIA. Correlation between aortic arch geometry and blood pressure at rest Twenty-seven patients (25.7%) were hypertensive at rest. Hypertension was more frequent in patients with gothic arch geometry (20/44, [45.5%, 95%CI ]) than in crenel form (5/18, [27.8% 95%CI ]) and in normal form (2/43, [4.6%, 95%CI ]) (P < 0.001) (Fig. 2). In univariate analysis, age at operation, age at time of the study, weight, height, arm-leg systolic BP gradient, and A/T were significantly higher in the HT group compared to the N group (Table 3). Using multiple logistic regression analysis, the only independent factor associ-

5 Late systemic hypertension and aortic arch geometry after successful repair of coarctation of the aorta 1857 Table 3 Comparison of clinical and geometric variables in the HT and N groups HT N P n (total = 105) Sex M/F 20/7 47/ Age (years) 17.3 ± ± Weight (kg) 57.1 ± ± Height (cm) ± ± Age at operation (months) 41.2 ± ± Follow-up since surgery (years) 14.6 ± ± Systolic BP (mmhg) ± ± 12.7 < Diastolic BP (mmhg) 66.5 ± ± Pulse pressure (mmhg) 77.6 ± ± 14.5 < Arm-leg systolic BP gradient (mmhg) 7.6 ± ± A/T 0.83 ± ± 0, Residual stenosis (%) 23.3 ± ± Aortic arch growth index 0.7 ± ± Left ventricular mass index (g/m 2 ) 99.4 ± ± ated with the HT status was the gothic arch geometry (P = 0.02) when the independent variables used in the model were age at operation, age at time of the study, weight, height, arm-leg systolic BP gradient, and the geometry category. When the continuous variable A/T was used in the model instead of the geometry category, the only independent factor associated with the HT status was A/T (P = 0.04). We also compared the level of resting systolic BP between the three geometries of the aortic arch. As shown in Table 2, systolic BP was significantly higher in the gothic arch geometry (P < ). Using analysis of covariance with the same independent variables, the only correlate with systolic BP was the gothic arch geometry (P = 0.04). When the continuous variable A/T was used in the model instead of the geometry category in multiple linear regression analysis, the only correlate with systolic BP was A/T (P = 0.009). Correlation between aortic arch geometry and left ventricular mass Left ventricular mass index was higher in patients with gothic arch geometry (Table 2) and in the HT group (Table 3). There was no difference between crenel and normal forms. In univariate regression analysis, there was a positive correlation between LVMI and age at surgery, age at time of the study, height, weight, systolic BP, PP, and A/T. In multiple linear regression analysis or analysis of covariance with the same independent variables, only gothic arch geometry (P = 0.004) and A/T (P = 0.007) were correlated to LVMI. Discussion Persistent or recurrent systemic hypertension is the major long-term complication after successful repair of aortic CoA in infancy. 1 4,16,17 Factors contributing to hypertension after CoA repair are numerous and intricate. 5,18,19 The patients included in our study were considered to have good clinical and anatomical result for their CoA repair. None exhibited the two known anatomical factors in exercise-induced and resting hypertension, namely residual stenosis 14 and aortic arch hypoplasia. 20 We have shown, however, that a peculiar gothic geometry of the aortic arch was strongly associated with hypertension at rest in patients having undergone successful repair of CoA. This finding is a potential relevance for the development of clinical complications in outcome, even in these patients with a good anatomical result from surgery. Geometry of the aortic arch We defined three types of aortic arch geometry: gothic, crenel and normal. As these were determined only on the basis of the general aspect of the aortic arch on MRI, we used a continuous variable, A/T, to define the disproportion between the aortic arch width and height. A/T was an interesting marker of the aortic arch geometry, as it was not correlated with age. Mechanisms leading to gothic arch geometry are unknown. We observed that the gothic geometry was not associated with a specific type of CoA repair. Indeed, the extended aortic arch anastomosis increases the size of the aorta between the left carotid and the left subclavian artery, but does not usually enlarge the portion between the innominate and the left carotid artery, and could therefore lead to a gothic geometry of the aorta. 21 While the majority of our patients with gothic arch had had this type of repair, there still remained those who had undergone classical end-to-end anastomosis or subclavian flap aortoplasty. As patients with gothic arch geometry were older than those in the other two groups, this form may be acquired during growth. End-to-end anastomosis does not enlarge the small horizontal aorta proximal to the CoA, but according to the haemodynamic moulding theory, relief of CoA in young infants does promote growth in its diameters. 22 While growing in width,

6 1858 P. Ou et al. this segment may not grow in length, thus, leading to a gothic geometry with normal diameters of aortic arch segments. Geometry and hypertension In our series, systolic BP at rest was positively correlated with A/T and patients with gothic geometry had significantly higher systolic BP. In addition, the gothic arch geometry and A/T were also found to be associated with increased pulse pressure, the latter being a strong independent predictor of cardiovascular events. 23 As it has been suggested that hypertension seems not to be related to residual stenosis, but rather to discrepancies in the growth of the transversal aortic arch proximal to the repair site, 20 we used an index of aortic arch growth to assess discrepancy among the diameters of different aortic arch segments adapted from previous works. 21,24 26 No correlation was found between hypertension at rest and aortic arch growth index or the percentage of residual stenosis, thus attesting to good CoA repair and aortic arch growth in our patients. The pathophysiology of late hypertension in patients subsequent to repair of CoA is probably multifactorial. 5 The novel finding in our study includes an important role of abnormal shape of the aortic arch related to resting hypertension in patients who have undergone successful repair of CoA. As it has been shown in reconstructed aorta, 27 gothic arch geometry might have disturbance of fluid dynamics in the ascending aorta. In addition, it has been shown that vascular remodelling is an adaptive process that occurs in response to long-term changes in haemodynamic condition. 28 Haemodynamic changes in gothic arch, thus, might contribute to resting hypertension because of changes in arterial pressure wave propagation and/or increase in aortic stiffness. Vascular remodelling to haemodynamic stimuli might contribute to upper limb conduit artery dysfunction, associated with structural abnormalities of the arterial wall, such as increased collagen and reduced elastin content. 29 Gothic arch might also contribute to an abnormal response in blood pressure regulation because of potential baroreceptor dysfunction when the transverse aortic arch is shortened or absent. All these potential mechanisms that might influence resting BP, including resetting of the sympathetic nervous and/or renin angiotensin system, still need further investigation in these selective patients with gothic arch geometry. Geometry, hypertension: left ventricular and arterial consequences Left ventricular mass is an important predictor of cardiovascular outcome in the general population, independent of BP. 30 In addition, it is known that there is a continuous relation between left ventricular mass and risk of cardiovascular disease in subjects with uncomplicated essential hypertension over a wide range of values. 31 In our series, as in previous studies, 12,32 there was an association between left ventricular mass index and age, body height and weight, and systolic BP after successful repair of aortic coarctation. Furthermore, multivariate analyses demonstrated that gothic arch geometry or A/T had significant influence on LVMI, independent of age and resting systolic BP, suggesting chronic increase in left ventricle after load in this peculiar gothic arch geometry. There are several possible explanations for the increase left ventricular mass in this condition. It might be an adaptation of haemodynamic changes that is probably encountered in the gothic arch. As previously mentioned, these might include changes in arterial pressure wave and/or an increase in aortic stiffness. Increase of left ventricular mass might also be determined by hormonal differences that persist even after successful repair. These include resetting of the sympathetic nervous and/or renin angiotensin system. Therapy How to treat these patients remains unresolved. Prevention of gothic geometry of the aortic arch during repair is difficult. The patch aortoplasty, which would be appropriate, is not recommended in young infants because of the high risk of aneurysm formation. 33 Re-operation to restore normal morphology is dangerous, as it requires circulatory arrest with selective brain perfusion and there is no development of collateral circulation in the absence of residual obstruction for brain protection. While operation is not recommended, patients with gothic geometry should have close follow-up to detect resting hypertension. Limitations of the study Some patients in the HT group had either normal or crenel geometry. Therefore, the different parameters that we studied are not the only contributing factors to resting hypertension. Aortic blood flow patterns related to geometrical parameters may play a role. 27 Velocity measurements can be made using MRI, 34,35 and should be taken at the same time as geometrical assessment of the aortic arch. Velocity profiles and mechanical aortic properties including compliance and distensibility of the ascending aorta could then be assessed and compared to the geometry of the aortic arch. We are currently evaluating these parameters in our patients and plan to do a longitudinal follow-up to determine if the prevalence of gothic geometry increases with age. Conclusion In patients with good coarctation repair, systemic hypertension at rest is related to the gothic form of the aortic arch, which can be expressed by an elevated height/ width ratio of the thoracic aorta. As MRI is routinely used to study growth of the aortic arch after CoA repair, patients with this morphology should have regular followup to assess the timing of hypertension occurrence. Intermediate endpoints may be required to assess this

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