Repaired coarctation of the aorta, persistent arterial hypertension and the selfish brain

The local Research Ethics committee confirmed that the study conformed to the governance arrangements for research ethics committees. A retrospective review of a prospectively maintained clinical database of consecutive patients with a history of CoA, > 16 years, undergoing routine clinical cardiovascular magnetic resonance (CMR) surveillance as part of their first presentation to the Adult Congenital Heart Disease Unit within the Bristol Heart Institute between 1999 and 2015 was performed. All patients provided written informed consent for their images to be used for research. Exclusion criteria included non-diagnostic intracranial time-of-flight magnetic resonance angiography (MRA) and subjects who did not undergo CoA repair or who were lost to follow-up (Fig. 1). Baseline demographic and clinical characteristics were recorded from electronic chart review including age and type of CoA repair, a documented diagnosis of hypertension and drug therapy. Where details of specific CoA repair type were missing or ambiguous (n = 27), e.g. where the repair was performed in an outside institution and the original operation note was not available, were excluded from subgroup analysis of the impact of repair type on VAH + ipCoW (Fig. 1). Average office systolic (SBP) and diastolic blood pressures (DBP) were acquired using an automated cuff (Omron Corporation, Kyoto, Japan), in accordance with International hypertension guidelines [13]. Uncontrolled hypertension was defined as office BP > 140/90 mmHg despite at least 2 anti-hypertensive medications [13]. Data from age and sex-matched normotensives, a subgroup from a prior research study [12], were used as a control group.

Aortic MRA had been performed in all repaired CoA subjects to assess for repair site complications. Briefly, following the injection of 0.1 mmol/kg of intravenous gadobutrol (Gadovist, Bayer Pharma AG, Berline, Germany), a 3D systemic arterial MRA at 1.5 T (Avanto, Siemens Healthineers, Erlangen, Germany) from thoracic apex to groins was acquired (TR/TE = 3.1/10.9 ms, flip angle = 25 degrees, voxel size = 1.1x1x1mm, matrix 448 × 265). Intracranial time of flight MRA is routinely performed at the time of first presentation imaging surveillance in all new subjects with history of repaired CoA presenting to our Adult Congenital Heart Disease Unit to screen for intracranial aneurysms as previously described [14]. In brief, a 3D time-of-flight MRA at 1.5 T (Avanto, SiemensHealthineers) with dedicated head coil to assess arterial anatomy (TR 38 ms, TE 5.28 ms, flip angle 25 degrees, voxel size 0.7 × 0.5 × 0.8 mm, field of view 200 mm, covering major arteries feeding into the circle of Willis. The normotensive controls were scanned using 3 T (GE HDx, General Electric Healthcare, Waukesha, Wisconsin, USA) to generate a 3D time-of-flight MRA (TR/TE 24/2.7 ms flip angle 20 degrees, voxel size 0.34 × 0.34 × 0.5 mm³, field of view 192x192x85 mm³).

Source aortic MRA data were routinely reported by a consultant cardiovascular radiologist and retrospectively independently reviewed by an imaging cardiologist with > 2 years’ experience blinded to clinical details, including CoA repair type, degree of residual narrowing and normotensive/hypertensive state. As previously described [15, 16], re-coarctation was defined when the diameter of the repaired CoA segment divided by the diameter of the descending thoracic aorta at the diaphragmatic hiatus was < 40%. Re-coarctation on imaging could not be directly assessed in stent repair due to artifact. However, there were no clinical features (such as arm-leg SBP discrepancy) to suggest a clinically relevant re-coarctation in any post-CoA repair subjects. Arch hypoplasia was assessed by the ratio of the minimum mid aortic arch diameter to the descending thoracic aorta at the level of the left atrium, as previously [17]. Multi-planar reformatted gadolinium-enhanced aortic MRA images were also reviewed for the presence of renal artery stenosis, defined as as > 50% focal reduction in vessel diameter [18].

Source MRA data were reviewed in 3 orthogonal multiplanar reformatted (MPR) planes with cross-referencing of images. Maximum intensity projection images were generated and reviewed. Scans were routinely reported by a consultant cardiovascular radiologist and retrospectively independently reviewed by a radiologist with > 3 years’ experience blinded to clinical details, including CoA repair type, degree of residual narrowing and normotensive/hypertensive state. Discrepancies were resolved by consensus. All MRAs were reviewed on dedicated workstations (Insignia Medical Systems, United Kingdom). The visualised V2 (portion in the vertebral columns), V3 (after exit from the C2 transverse foramen) and V4 (the intracranial portion beginning at the atlanto-occipital membrane and terminating at the basilar artery) segments were analysed. VAH was defined as a diameter < 2 mm uniformly throughout the vessel, and not if only a focal narrowing was presented suggestive of atherosclerotic steno-occlusive disease, as previously described (Fig. 2) [19]. CoW anatomy was classified as previously described [20]. Briefly, vessels that were visualized as continuous segments of at least 0.8 mm in diameter were considered present and those smaller than 0.8 mm in diameter were considered hypoplastic [20]. These predefined caliber thresholds facilitated direct comparison between 1.5 T and slightly higher resolution 3 T MRA datasets. Care was taken to distinguish the posterior communicating arteries from the anterior choroidal arteries by cross-referencing MPR images. The communication of the posterior communicating artery with the posterior cerebral artery was confirmed for all posterior communicating arteries identified. The posterior aspect of each CoW was assessed for morphology and classified as previously described [20]. Incomplete posterior CoW was defined as either unilateral or bilateral hypoplastic or absent posterior communicating arteries or unilateral or bilateral hypoplastic or absent pre-communicating segment of the posterior cerebral artery or a combination thereof (Fig. 3).

Statistical analysis was performed using SPSSv.21 (Statistical Package for the Social Sciences (SSPS), International Business Machines, Inc., Armonk, New York, USA). An overall sample size of 49 provides a power of > 80% to find a 27% difference (estimated from a prior study [12]) in the prevalence of VAH between the two groups, with a two-sided type one error of 0.05. All data analysis was blinded. Normality was determined by the Shapiro-Wilks test. Differences between: 1) controls and CoA subjects and 2) CoA subjects with VAH + ipCoW and CoA subjects without VAH + ipCoW were assessed by unpaired Students t-tests, independent samples Mann-Whitney U tests or Fisher’s exact tests as appropriate. Binary logistic regression analysis was performed to determine differences, controlling for age, male gender and body mass index (BMI), in odds ratios for: 1) the presence of VAH + ipCoW in CoA compared to normotensives and 2) the presence of a diagnosis of hypertension in subjects with VAH + ipCoW compared to those without. Differences in prevalence of VAH + ipCoW between CoA hypertensive and non-hypertensive subgroups was assessed with a Fisher’s exact test. Univariate and multivariate regression analysis was performed to assess for determinants of VAH + ipCoW in repaired CoA subjects. Where appropriate, data are reported as mean ± standard deviation, median with range, as a percentage or odds ratio with 95% confidence intervals. All statistical tests were two-tailed. Significance was set at P <  0.05.

We addressed the question: does VAH and ipCoW occur more frequently in repaired CoA subjects, a requisite if the “selfish brain” hypothesis is implicated in the development of hypertension following repaired CoA. Odds ratios from multivariate logistic regression analysis, controlling for age, male gender and BMI, showed that patients with repaired CoA (n = 127) were 5.8 times more likely to have VAH + ipCoW than controls (n = 33)(β: 5.795, 95th CI: 1.614–20.812, p = 0.007) but age (β: 1.013, 95th CI: 0.985–1.041, p = 0.37), male gender (β: 1.429, 95th CI: 0.681–2.999, p = 0.35) and BMI (β: 1.038, 95th CI: 0.966–1.115, p = 0.31) were not significant predictors of VAH and ipCoW.

Next, we sought to answer the question: does VAH + ipCoW predict hypertension following CoA repair? Prevalence of VAH and ipCoW in coarctation with hypertension (n = 64) was significantly higher than controls (n = 33) (44% vs 9%, p <  0.0001, Fisher’s exact test). Additionally, the prevalence of VAH and ipCoW in coarctation without hypertension or anti-hypertensive medication (n = 63) was significantly higher than controls (n = 33) (29% vs 9%, p = 0.037, Fisher’s exact test). There were no differences in percentage restenosis at the site of CoA repair (17 ± 27% vs 16 ± 19%, p = 0.74) or degree of arch hypoplasia (arch hypoplasia index: 0.79 ± 0.20 vs 0.76 ± 0.17, p = 0.32) between repaired CoA cohorts with or without hypertension. However, there was only a trend towards higher prevalence of hypertension in repaired CoA with VAH + ipCoW compared to those without (61% vs 44%, p = 0.097) but repaired CoA subjects with VAH + ipCoW had higher SBP (145 ± 20 vs 134 ± 18 mmHg, p = 0.003) despite more having anti-hypertensive medications prescribed (54% vs 33%, p = 0.025). Furthermore, repaired CoA subjects with VAH + ipCoW and hypertension were older than those without hypertension (38 ± 11 vs 30 ± 12 years, p = 0.035).

Not all subjects with repaired CoA have VAH + ipCoW. Subgroup analysis comparing repaired CoA subjects without VAH + ipCoW (n = 81) and subjects with VAH + ipCoW (n = 46) was performed to determine if these cerebrovascular variants were associated with higher BP and uncontrolled hypertension. The subgroup analysis is presented in Table 2. Odds ratios from binary logistic regression showed that when VAH + ipCoW were present, subjects were 3.3 times more likely to have treated uncontrolled hypertension (β: 3.286, 95th CI: 1.005–10.743, p = 0.049).

Not all subjects with repaired CoA and VAH + ipCoW had hypertension. Subgroup analysis demonstrated that subjects with repaired CoA, VAH + ipCoW and hypertension (n = 28) were significantly older than subjects with repaired CoA, VAH + ipCoW without hypertension (n = 18) (38 ± 11 vs 30 ± 12 years, p = 0.035, Student’s t-test) but there were no significant differences in BMI (26 ± 5 vs 26 ± 7 kg/m², p = 0.99, Student’s t-test) or sex (75% (21/28) male vs 56% (10/18) male, p = 0.21, Fisher’s Exact test). There were no significant differences in prevalence of repair types between repaired CoA with VAH + ipCoW and hypertension compared to those without hypertension. In addition, Amongst subjects with repaired coarctation but without VAH + ipCoW, those with hypertension were older than those still normotensive (37 ± 15 vs 29 ± 11 years, p = 0.013, Student’s t-test).

Finally, we sought to determine whether the presence of VAH and ipCoW in repaired CoA was related to the either the age at time of repair or the type of CoA repair. In the subgroup of patients with adequate clinical history of time and type of repair (n = 100), age at time of repair was not a predictor of VAH and ipCoW in univariate or multivariate analysis, accounting for gender and BMI (Table 3). None of the types of repair (end to end anastomosis, subclavian flap repair, patch repair, balloon / stent angioplasty) (Fig. 4) were predictors of VAH + ipCoW in univariate analysis (Table 3).