Even after successful repair, hypertension is one of the main determinants of cardiovascular morbidity and mortality in patients with aortic coarctation (CoA). We compared the effect of candesartan (angiotensin II receptor blockade) and metoprolol (β-adrenergic receptor blockade) on blood pressure, large artery stiffness, and neurohormonal status in hypertensive patients after repair of CoA. In the present open-label, crossover study, hypertensive patients after CoA repair were first randomly assigned to treatment with candesartan 8 mg or metoprolol 100 mg once per day. After 8 weeks of treatment with one of the drugs, the other treatment was given for 8 weeks. The treatment effects were assessed with 24-hour ambulatory blood pressure monitoring, measurement of large artery stiffness, and neurohormonal plasma levels at baseline and after 8 weeks of either treatment. Sixteen patients (mean age 37 ± 12 years, 26 ± 15 years after repair, 63% men) completed the study. The 24-hour mean arterial pressure at baseline was 97.7 ± 6.2 mm Hg. Metoprolol (mean dose 163 ± 50 mg/day) decreased the mean arterial pressure (7.0 ± 4.2 and 4.1 ± 3.6 mm Hg, respectively) more than did candesartan (mean dose 13 ± 4 mg/day; p = 0.018, 95% confidence interval 0.6 to 5.5). Large artery stiffness did not change with either treatment. With metoprolol, plasma B-type natriuretic peptide increased and plasma renin decreased. With candesartan, the plasma renin and noradrenaline levels increased and aldosterone levels decreased. In conclusion, in adult hypertensive patients after CoA repair, metoprolol had more of an antihypertensive effect than did candesartan. Moreover, the neurohormonal outcome did not support a significant role for the renin-angiotensin system in the causative mechanism of hypertension after CoA.
Hypertension is one of the main determinants of cardiovascular morbidity in patients with successfully repaired coarctation of the aorta (CoA). The prevalence of late systolic hypertension in adults 10 to 20 years after repair is 30%, and at 30 years postoperatively, it increases to approximately 68%. The exact cause of this hypertension remains unknown. The potential causes are structural and functional abnormalities of the precoarctation arterial wall with decreased compliance. For instance, increased collagen and decreased smooth muscle mass in the aortic wall are believed to result in diminished arterial wall compliance and increased rigidity. Furthermore, hypertension could occur because of impaired baroreflex sensitivity. Although extensive research on the causes of late hypertension has been performed, no data are yet available on the specific treatment for patients with CoA, even though such knowledge could contribute to the understanding of the causative mechanism. β Blockers are the most commonly used antihypertensive agents in patients after CoA repair. Some investigators have recommended angiotensin-converting enzyme inhibitors as the first-choice treatment from evidence that angiotensin-converting enzyme inhibitors improve pulsatile hemodynamics and regress left ventricular hypertrophy. In other patient groups, angiotensin II type 1 receptor blockers have been as effective and have fewer side effects. Moreover, angiotensin II type 1 receptor blockers, like angiotensin-converting enzyme inhibitors, can have favorable effects on large artery stiffness. In the present, crossover study, we investigated the effect of the angiotensin II type 1 receptor blocker candesartan and the β blocker metoprolol on blood pressure (BP) in patients after repaired CoA. In addition, the effect of the 2 drugs on large artery stiffness and changes in neurohormonal status was studied to define the optimal treatment and to provide additional insight into the causative mechanism of late hypertension in patients after CoA repair.
Methods
In the present single-center, prospective, randomized, open-label crossover study, all patients provided informed consent. The hospital’s medical ethics committee approved the study. A total of 18 adult patients after repair of CoA who had been diagnosed with hypertension were included. Hypertension was defined as systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg and/or current use of antihypertensive medication. Patients with a known intolerance to candesartan or metoprolol, with significant liver insufficiency (alanine aminotransferase or aspartate aminotransferase >3 times the upper limit of normal), currently using ≥3 antihypertensive drugs, who were pregnant or wished to become pregnant during the study, with evidence of repeat CoA (arm-to-leg BP gradient ≥20 mm Hg), or with general contraindications to candesartan or metoprolol were excluded. When a gradient ≥20 mm Hg was found, magnetic resonance imaging was performed (5 patients) to exclude repeat CoA.
The patients with a current use of antihypertensive medication were enrolled after a washout period of 3 weeks. Patients were first randomly assigned to treatment with candesartan 8 mg/day first (group A) or metoprolol 100 mg/day (selokeen ZOC, group B). After 8 weeks of treatment with one of the drugs, another washout period of 3 weeks was arranged. Subsequently, the other drug was given for 8 weeks. Measurements of 24-hour ambulatory blood pressure monitoring (ABPM), aortic and carotid stiffness, and vasoactive hormone plasma levels were performed after both periods of washout and after 8 weeks of medication use. After completing the study, the patients were asked about any adverse effects and their medication preference.
The BP responses to treatment were measured after both periods of washout and after 8 weeks of either treatment using the right arm and 24-hour ABPM. ABPM measurements were recorded using a Spacelabs 90207-30 or Spacelabs 90-217-9Q device (Spacelabs Healthcare, Issaquah, Washington). The recordings were performed every 30 minutes during the day (7:00 a.m. to 10:00 p.m. ) and every 60 minutes during the night (10:00 p.m. to 7:00 a.m. ). The monitor display was switched off during ABPM to avoid any possible effect on the BP readings. Four weeks after starting the medication, a single BP measurement was performed at the patient’s general practitioner’s office or at the outpatient clinic. For ethical reasons, the medication dose was doubled if the systolic BP was ≥140 mm Hg and/or the diastolic BP was ≥90 mm Hg.
Aortic stiffness was measured with the patient in the supine position using the carotid-femoral pulsewave velocity (PWV). The PWV was assessed with a noninvasive automatic device (Complior SP, Artech Medical, Pantin, France) that measures the time delay between the beginning of the rapid upstroke of the simultaneously recorded pulse waves in the carotid and femoral arteries. The distance between the throat and the femoral artery was measured. The PWV was calculated as the ratio between that distance and the foot-to-foot time delay and was expressed in meters per second.
Carotid distensibility was assessed with the patients in the supine position, with the head turned slightly in the contralateral position for measurement at the right common artery. The vessel wall motion of the artery was measured using a duplex scanner (ATL Ultramark IV, 7.5 MHz probe, Soma Technology, Bloomfield, Connecticut) connected to a vessel wall movement detector system. This is a validated technique for the measurement of carotid distensibility. A region 1.5 cm proximal to the origin of the bulb of the carotid artery was identified using B-mode ultrasonography. The displacement of the arterial walls was obtained by processing the radiofrequency signals originating from 2 selected sample volumes positioned over the anterior and posterior walls. The end-diastolic diameter (D), the absolute change in diameter during systole (ΔD), and the relative change in diameter (ΔD/D) were computed as the mean of 4 cardiac cycles. The cross-sectional arterial wall distensibility coefficient was calculated according to the following equation: distensibility coefficient = [2ΔD / (D × pulse pressure) (10 −3 /kPa)].
Blood samples were taken for measurement of B-type natriuretic peptide (BNP), renin, aldosterone, catecholamines, and endothelin-1. An intravenous cannula was inserted in one of the forearm veins, and blood samples were obtained after the patient had been in the supine position for 30 minutes. The BNP, renin, aldosterone, and endothelin-1 levels were determined with commercially available kits, as previously described. Noradrenaline and adrenaline were measured with fluorimetric detection after high-performance liquid chromatography.
Normally distributed continuous data are presented as the mean ± SD and categorical variables as counts and percentages. Non-normally distributed data, including neurohormonal status, are presented as the median with the interquartile range (twenty-fifth and seventy-fifth percentiles). The baseline (pretreatment) values were established after a washout period of 3 weeks. The change (Δ) was calculated as the value after treatment minus the value before treatment. The difference in the change (Δ) between the 2 treatments was used to analyze the effect of the 2 treatment regimens using the paired Student t test (2 tailed) for continuous variables, when normally distributed. The Wilcoxon signed ranks test was considered for the skewed distributed of neurohormonal status. All statistical tests were 2-sided, and p <0.05 was considered statistically significant. Statistical analyses were performed using the Statistical Package for Social Sciences, version 15.0, for Windows (SPSS, Chicago, Illinois).
Results
The baseline characteristics of the study population are listed in Table 1 . A total of 18 patients were included in the study, and 16 patients (89%, mean age 37 ± 12 years, 63% male) completed the study successfully. The reasons for not completing the study were respiratory distress provoked by β blockade (n = 1) and noncompliance (n = 1). None of the participating patients were smokers or had diabetes. The treatment dosage of both candesartan (mean dose 13 ± 4 mg/day) and metoprolol (mean dose 163 ± 50 mg/day) was doubled after 4 weeks in 10 patients; in the remaining 6 patients, the initial dosage was continued for both drugs.
| Pt. No. | Gender | Age (yrs) | Interval After Repair (yrs) | BMI (kg/m 2 ) | Repair Type | Repeat Intervention | Additional Congenital Cardiac Anomalies | Antihypertensive Treatment Before Study | Arm-to-Leg Gradient (mm Hg) | Evidence of Repeat CoA on MRI |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Male | 20 | 0 | 31 | E/E | Yes | ASD | Yes | 10 | No |
| 2 | Male | 20 | 1 | 24 | E/E | No | VSD, MR | No | 30 | No |
| 3 | Male | 20 | 7 | 22 | E/E | No | None | No | 0 | Unknown |
| 4 | Female | 25 | 0 | 24 | SC flap | No | None | Yes | 9 | Unknown |
| 5 | Male | 28 | 19 | 22 | E/E | No | BAV | Yes | NA | No |
| 6 | Female | 30 | 0 | 23 | E/E | No | BAV, PDA | Yes | 0 | Unknown |
| 7 | Male | 33 | 9 | 35 | Patch | No | None | Yes | 0 | Unknown |
| 8 | Male | 38 | 20 | 27 | Patch | No | VSD | Yes | 2 | Unknown |
| 9 | Male | 39 | 32 | 23 | Graft | No | AR | Yes | 0 | Unknown |
| 10 | Female | 41 | 40 | 29 | Stent | No | BAV, SVAS | Yes | 0 | Unknown |
| 11 | Male | 44 | 17 | 21 | Patch | Yes | BAV | No | 25 | No |
| 12 | Female | 46 | 17 | 27 | Patch | No | BAV | Yes | 0 | Unknown |
| 13 | Male | 48 | 6 | 26 | E/E | No | BAV, PDA, MR | Yes | 0 | Unknown |
| 14 | Female | 49 | 5 | 34 | Patch | Yes | None | Yes | 20 | No |
| 15 | Female | 50 | 5 | 24 | E/E | No | None | Yes | 0 | Unknown |
| 16 | Male | 61 | 7 | 27 | Unknown | Yes | None | Yes | 0 | Unknown |
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