Acquired von Willebrand Syndrome in an Infant With Coarctation of the Aorta and Williams Syndrome.

An infant with coarctation of the aorta and Williams syndrome was noted to have petechiae in cardiology clinic prior to planned surgical intervention. Workup revealed acquired von Willebrand syndrome secondary to the high shear force generated by the aortic coarctation. He was treated with intra- and postoperative Humate P; there were no postoperative bleeding complications. His acquired von Willebrand syndrome resolved postoperatively.

Impact of Treatment Modality on Vascular Function in Coarctation of the Aorta: The LOVE - COARCT Study.

Background Optimally treated patients with coarctation of the aorta remain at risk for late vascular dysfunction. The effect of treatment modality on vascular function is unknown. The LOVE-COARCT (Long-term Outcomes and Vascular Evaluation After Successful Coarctation of the Aorta Treatment) study was done to compare vascular function in patients with coarctation of the aorta treated with surgery, balloon dilation (BD), or stent implantation. Methods and Results In treated coarctation of the aorta patients without residual coarctation, we prospectively compared aortic stiffness by applanation tonometry and cardiac magnetic resonance; endothelial function by endothelial pulse amplitude testing; blood pressure ( BP ) phenotype by office BP , ambulatory BP monitoring, and BP response to exercise; left ventricular mass by cardiac magnetic resonance; and blood biomarkers of endothelial function, inflammation, vascular wall function, and extracellular matrix. Participants included 75 patients treated with surgery (n=28), BD (n=23), or stent (n=24). Groups had similar age at enrollment, coarctation of the aorta severity, residual gradient, and metabolic profile, but differed by age at treatment. Prevalence of systemic hypertension, aortic stiffness, endothelial function, and left ventricular mass were similar among treatment groups. However, BD patients had more-distensible ascending aortas, lower peak systolic BP during exercise, less impairment in diurnal BP variation, and lower inflammatory biomarkers. Results were unchanged after adjustment for potential confounders, including age at treatment. Conclusions In our cohort of patients without residual coarctation, treatment modality was not associated with major vascular outcomes, even though there were some favorable vascular characteristics in the BD patients. Although this suggests that choice of treatment modality should continue to be driven by likelihood of achieving a good anatomical result, more long-term studies are required to assess the clinical significance of the more-optimal results of secondary markers of vascular function in BD patients. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 03262753.

Effects of atorvastatin on endothelial function and the expression of proinflammatory cytokines and adhesion molecules in young subjects with successfully repaired coarctation of aorta.

OBJECTIVE: To investigate the effects of atorvastatin on endothelial function and low-grade systemic inflammation in subjects with successful surgery for aortic coarctation repair (SCR). DESIGN: Open-label study. SETTING: Outpatients visiting the adult congenital heart disease department of our hospital. PATIENTS: 34 young people with SCR. INTERVENTIONS: Patients with SCR received atorvastatin 10 mg/day (n=17) or no treatment (n=17) for 4 weeks. At baseline and at 4 weeks, endothelial function was assessed by flow-mediated dilatation (FMD) of the right brachial artery, and blood samples were obtained. Serum levels of interleukin (IL) 1b, IL-6 and soluble vascular cell adhesion molecule-1 (sVCAM-1) were determined by ELISA. MAIN OUTCOME MEASURES: Effects of treatment on FMD and serum levels of IL-1b, IL-6 and sVCAM-1. RESULTS: FMD in the atorvastatin group was significantly improved after 4 weeks (from 6.46±0.95% to 11.24±1.38%, p<0.01), while remaining unchanged in the control group (from 6.74±0.58% to 6.95±0.53%, p=NS). Even though atorvastatin had no effect on serum IL-6 levels (0.62 (0.37-0.88) pg/ml to 0.53 (0.28-0.73) pg/ml, p=NS), it significantly reduced circulating levels of IL-1b (from 1.17 (0.92-1.77) pg/ml to 1.02 (0.75-1.55) pg/ml, p<0.05) and sVCAM-1 (from 883.4 (660.3-1093.1) ng/ml to 801.4 (566.7-1030.2) ng/ml, p<0.05). No changes were seen in serum levels of IL-6, IL-1b and sVCAM-1 in the control group after 4 weeks compared with baseline (p=NS for all). CONCLUSIONS: Atorvastatin treatment for 4 weeks in subjects with SCR significantly improved endothelial function and suppressed systemic inflammatory status by decreasing circulating levels of IL-1b and sVCAM-1.

Changes in cerebral oxygen saturation and blood flow during hypoxic gas ventilation therapy in HLHS and CoA/IAA complex with markedly increased pulmonary blood flow.

BACKGROUND: Hypoxic gas ventilation therapy has recently been performed to prevent post-birth increased pulmonary blood flow in cases of congenital heart diseases with increased pulmonary blood flow. However, how the oxygen supply to the tissues changes during breathing a hypoxic gas mixture, remains unknown. The changes in cerebral oxygen saturation and blood supply during hypoxic gas ventilation therapy using a nitrogen gas mixture were studied. METHODS AND RESULTS: Cerebral regional oxygen saturation (cerebral rSO(2)) was measured by near-infrared spectroscopy, and changes in middle cerebral artery (MCA) blood flow and an index of vascular resistance (RI) were assessed in 8 consecutive patients having congenital heart diseases with increased pulmonary blood flow. In all patients, urinary volume increased significantly, and the respiratory rate showed a clear decrease. Percutaneous oxygen saturation showed no significant change. The average of cerebral rSO(2) was 67.3% before hypoxic gas ventilation, but increased to 69.4%, 69.1%, and 70.7% within 1, 12, and 24 h after initiation of treatment, respectively. MCA blood flow significantly increased in the diastolic phase, and RI significantly improved from 0.80 to 0.68 within 12 h after initiation of therapy. CONCLUSIONS: These results indicate that hypoxic gas ventilation therapy does not decrease cerebral oxygen saturation, but safely improves the cerebral blood supply in cases of congenital heart diseases with increased pulmonary blood flow.

Comparison of Candesartan versus Metoprolol for treatment of systemic hypertension after repaired aortic coarctation.

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 (beta-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.

Effects of ramipril on endothelial function and the expression of proinflammatory cytokines and adhesion molecules in young normotensive subjects with successfully repaired coarctation of aorta: a randomized cross-over study.

OBJECTIVES: The purpose of this study was to evaluate the effect of ramipril on endothelial function and inflammatory process in a group of normotensive subjects with successfully repaired coarctation of the aorta (SCR). BACKGROUND: Subjects with SCR experience higher long-term cardiovascular risk as a result of the relapse of arterial hypertension or owing to nonreversible structural changes in the pre-coarctation arterial tree. These subjects experience endothelial dysfunction in the right forearm and appear to have elevated levels of proatherogenic inflammatory markers, even in the absence of arterial hypertension. METHODS: Twenty young individuals age 27.3 +/- 2.4 years old with SCR 13.9 +/- 2.2 years previously, received ramipril 5 mg/day for 4 weeks in a randomized, cross-over, controlled trial. Endothelial function was evaluated in the right forearm by gauge-strain plethysmography, and serum levels of interleukin (IL)-1b, IL-6, soluble CD40 ligand (sCD40L), and soluble vascular cell adhesion molecule (sVCAM)-1 were determined by enzyme-linked immunosorbent assay. RESULTS: Ramipril improved endothelial function (p < 0.001) and decreased the expression of proinflammatory cytokine IL-6 (p < 0.05) and sCD40L (p < 0.01). Furthermore, ramipril decreased serum levels of sVCAM-1 (p < 0.01) but failed to affect serum levels of C-reactive protein. These effects were independent of blood pressure lowering. CONCLUSIONS: Ramipril reversed the impaired endothelial function and decreased the expression of proinflammatory cytokine IL-6, sCD40L, and adhesion molecules in normotensive subjects with SCR. These findings imply that ramipril treatment may have antiatherogenic effects in subjects with SCR, even in the absence of arterial hypertension.

Evaluation of immunomodulatory biomarkers in a pressure overload model of heart failure.

STUDY OBJECTIVES: To characterize the immunomodulatory response in a pressure overload model of heart failure, and to further validate this animal model of human heart failure. DESIGN: Randomized, controlled, animal study. SETTING: Large university research facility. ANIMALS: Twenty-seven, male, Sprague-Dawley rats. INTERVENTION: The rats underwent either aortic constriction or a sham procedure. MEASUREMENTS AND MAIN RESULTS: Six months after the surgical procedure, echocardiographic measurements were obtained, the animals were sacrificed, and plasma samples were taken to measure concentrations of biomarkers. As six (40%) of the 15 rats in the aortic-constriction group died before the 6 months, only nine rats from this group underwent immunomodulatory evaluation. Compared with the sham procedure, aortic constriction increased the left ventricle:body weight ratio in the rats (p=0.0016) It also decreased the velocity of circumferential shortening (p=0.08) and increased myocardial expression of atrial natriuretic factor, beta-myosin heavy chain, and fibronectin (p<0.05). Concentrations of the proinflammatory mediator interleukin (IL)-1beta and the counterregulatory mediator IL-10 also significantly increased (p<0.04) in the group that underwent aortic constriction compared with the group that underwent the sham procedure. Nonsignificant increases (mean change approximately 50-180%) were also observed for IL-2, IL-6, and leptin concentrations. CONCLUSIONS: In this classic animal model of heart failure, a systemic immunomodulatory response was evaluated after 6 months of pressure overload resulting in myocardial decompensation and, in some cases, mortality. The findings are similar to the immunomodulatory response that may be observed in human heart failure. These novel results further define this model of heart failure and suggest another aspect of its relevance to human heart failure with regard to pressure overload and the immunomodulatory response.

Exercise testing in adults after repair of aortic coarctation: evaluation of cardiopulmonary exercise capacity and B-type natriuretic protein levels.

The aim of the study was to investigate, in adult patients after successful repair of aortic coarctation, potential relationships between B-type natriuretic peptide levels and exercise capacity and the following factors: arterial hypertension, residual stenosis of the ascending aorta, and age at the time of surgery. The study group comprised 74 patients (45 men) aged 19 to 61 years (mean, 31.2 +/- 9.8 yr), who had undergone surgery at the age of 0.5 to 34 years (mean, 10.4 +/- 6.8 yr). The surgery was performed between 5 and 34 years earlier (mean, 21.4 +/- 6.2 yr). A subgroup with residual aortic stenosis (significant when > or =25 mmHg) comprised 32 patients; a subgroup without residual stenosis comprised 42 patients. Patients were also divided into subgroups without arterial hypertension (n=32), with exercise-induced arterial hypertension (n=10), and with persistent arterial hypertension (n=32). All patients were in New York Heart Association functional class I. The control group comprised 30 healthy subjects (18 men) aged 26 to 46 years (mean, 32.2 +/- 6.6 yr). After testing exercise capacity in accordance with a modified Bruce protocol, we concluded that the exercise capacity of adults is reduced after surgical repair of aortic coarctation. This reduction is more pronounced in patients who have arterial hypertension, but it is unaffected by residual stenosis of the descending aorta. Serum B-natriuretic peptide concentrations, as determined by immunoradiometric assay, are significantly elevated, which may result from pressure overload of the left ventricle or from residual myocardial lesions due to coarctation repair at an older age.

Soluble endothelial adhesion molecule concentration in patients with aortic coarctation.

Coarctation of aorta (CoA) is often associated with development of vascular abnormalities and hypertension despite successful correction. The aim of the study was to compare concentrations of adhesion molecules and interleukin-6 (IL-6), an inflammatory cytokine in following groups: children with CoA before operation, chidren with CoA after operation, and healthy control children. Seventeen children with CoA and 18 healthy children (control) were investigated. Blood samples were taken 1 day preoperatively and during followup (10.2+/-7.5 months). Serum concentrations of soluble E- and L-selectin, intercellular adhesion molecule-1 (sICAM-1), and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). On arms, systolic and diastolic blood pressures decreased after surgery. On legs, only systolic, but not diastolic, blood pressure increased significantly. There was no difference in the concentrations of IL-6, sE-, sL-selectin, or sICAM-1 before and after CoA repair. Postoperative ICAM-1 concentration in children with CoA was significantly higher compared to control (321.7+/-93.4 versus 248.8+/-84.3 ng/mL, P=.002). Only preoperative concentration of L-selectin was higher in children with CoA compared to control (1617.7+/-387.5 ng/mL versus 1271.1+/-266.6 ng/mL). The correction of CoA leads to normalization of leukocyte activity. The markers of endothelial damage and proinflammatory activity are not significantly changed by correction of CoA in young children.

An evaluation of acid-base changes following aortic cross-clamping using transcutaneous carbon dioxide monitoring.

To investigate the cause of acidosis following release of an aortic cross-clamp, we measured tissue PCO2 using a transcutaneous (TC) CO2 monitor placed below the level of the cross-clamp in 10 patients undergoing aortic arch surgery. Following placement of the aortic cross-clamp, the TC CO2 value from the lower extremity increased from 41 +/- 4 to 92 +/- 41, whereas there was no change in the TC CO2 value from the upper extremity. With release of the cross-clamp, end-tidal CO2 increased by 6.2 +/- 1.9 mmHg, the upper TC CO2 increased by 8.4 +/- 4.8 mmHg, and the lower extremity TC CO2 value returned to baseline. During cross-clamping, there was an increase in the base deficit of 4.3 +/- 2.9 when comparing the baseline arterial blood gas value with the one obtained after cross-clamp release (p = 0.0004). These data demonstrate that the acidosis occurring during aortic cross-clamping is a mixed metabolic and hypercarbic acidosis. Appropriate treatment includes the provision of adequate minute ventilation to ensure CO2 removal and the use of sodium bicarbonate based on the degree of metabolic acidosis demonstrated by arterial blood gas analysis.

Vascular and neuroendocrine components in altered blood pressure regulation after surgical repair of coarctation of the aorta.

STUDY OBJECTIVE: To investigate potential vascular and neuroendocrine determinants of altered blood pressure (BP) regulation in patients previously operated on for aortic coarctation. DESIGN, SETTING AND PATIENTS: We prospectively re-evaluated 45 patients operated on for aortic coarctation at Strasbourg University Hospital over a 13-year period. Four of these patients were less than 2 years old at the time of the operation and four were older than 20 years. Patient age and time since the operation were on average 21+/-13 years and 8+/-3 years, respectively. Surgery consisted of a resection with end-to-end anastomosis for 18 patients, angioplasty (8), prosthesis (4) or sub-clavian flap (15). RESULTS: Despite repair of the coarctation, about 40% of the patients showed an abnormal BP status at rest. The majority of these patients had uncomplicated borderline hypertension. The orthostasis test as well as the BP circadian rhythm were frequently abnormal. While the ankle/arm systolic pressure index measured at rest was generally within the normal range, diminished carotid-femoral pulse wave velocity was observed. Plasma adrenaline and aldosterone levels were elevated in about 50% of the patients examined. CONCLUSIONS: These new findings suggest that there are 'cause and effect' relationships between aortic structural and functional vascular abnormalities, and augmented plasma adrenaline and aldosterone in some patients after coarctation repair. These phenomena are likely to be involved in altered BP regulation and might result in recurrent hypertension.

Elevated arginine vasopressin and lowered atrial natriuretic factor associated with hypertension in coarctation of the aorta.

Impairment of humoral and neural regulation of blood pressure may contribute to preoperative and postoperative hypertension in coarctation of the aorta and may also affect the release of vasopressin and atrial natriuretic factor. Because vasopressin and atrial natriuretic factor have potent vasoactive effects, we measured plasma vasopressin and atrial natriuretic factor levels by radioimmunoassay before operation and for 5 days after operation in 11 patients aged 9 months to 12 years undergoing coarctation repair and in 12 control patients undergoing other cardiovascular operations. Six patients in the coarctation group required minimal antihypertensive therapy (group I) and five required prolonged intravenous antihypertensive therapy (group II). Before operation, vasopressin levels correlated with systolic blood pressure for all patients in the coarctation group (r = 0.83, p < 0.01) whereas atrial natriuretic factor levels did not. Before operation, atrial natriuretic factor levels were lower (28 +/- 5 vs 41 +/- 7 and 50 +/- 8 pg/ml, p < 0.05) and vasopressin levels were higher (28 +/- 6 vs 5.4 +/- 0.9 and 7 +/- 3 pg/ml, p < 0.05) in group II than in group I or control patients. Vasopressin levels were higher (p < 0.05) on the day of operation and on postoperative days 2 through 5 in group II than in group I and in control patients. Atrial natriuretic factor levels were lower during the day of operation in group II than in group I or in control patients (26 +/- 7 vs 51 +/- 16 and 50 +/- 7 pg/ml, p < 0.05) and remained lower than control values on postoperative days 1 and 3 through 5. Elevated vasopressin and lowered atrial natriuretic factor levels may contribute to preoperative and postoperative hypertension in coarctation.

Progressive vascular lesions in Williams-Beuren syndrome.

We report two patients with Williams-Beuren syndrome. The first patient showed no evidence of coarctation of the aorta at the first examination. Seven years later, she developed coarctation of the aorta. In the second patient, we found the progression of renal artery stenosis by serial angiography. We report that vascular lesions may be progressive in Williams-Beuren syndrome.

Effects of exercise on plasma renin, aldosterone and catecholamines before and after surgery for aortic coarctation.

The pre- and postoperative values of blood pressure, pulse rate, plasma renin activity, plasma aldosterone concentration and circulating catecholamines were studied in a group of 12 patients with uncomplicated aortic coarctation before and after exercise. Mean age of patients studied was 21.5 years. Postoperative studies were carried out on average 204 days after surgery. Following operation, both resting and exercising upper extremity pressures decreased. Six out of the 11 patients still had an abnormally high exercising blood pressure when compared with a normal control group of six persons. Postoperative pulse rates during exercise were significantly higher than pre-operatively (P less than 0.01). No statistically significant differences between pre- and postoperative values, and between patients and normal controls were found in the hormonal studies. This study suggests that the renin-aldosterone-system does not have a major role in the maintenance of the hypertension associated with coarctation of the aorta.

Preoperative and postoperative renin levels in coarctation of the aorta.

We studied plasma renin activity (PRA) in eight children before and after surgical correction of aortic coarctation. These eight children underwent a combination of low-sodium diet and diuresis before surgery, and PRA was measured shortly thereafter. Thirty-two to 51 months after successful surgical correction, PRA was measured again. The mean PRA was 21.4 +/- 1.3 ng/ml/hour (+/- SD) preoperatively and 5.5 +/- 1.5 ng/ml/hour postoperatively. These findings provide further evidence of the significance of increased renin-angiotensin activity in patients with aortic coarctation.

Hypertensive mechanisms in coarctation of the aorta. Further studies of the renin-angiotensin system.

The mechanisms of hypertension in coarctation remain to be clearly defined. In other hypertensive states, abnormal plasma renin activity (PRA) has been unmasked by the depletion of extracellular volume and the use of angiotensin antagonists. In a group of patients with coarctation, preoperative and postoperative evaluations of the renin-angiotensin system have been performed. Before operation, a group of patients with coarctation and a group of normal control subjects both underwent salt restriction followed by diuresis. A standard angiotensin antagonist (saralasin) test was performed on the patients with coarctation, and they demonstrated excessive renin-angiotensin activity compared to the control subjects. Following operation, paradoxical hypertension developed in all of the patients. Repeat saralasin test in these patients again revealed excessive angiotensin activity in the same patients as preoperatively. It appears that the renin-angiotensin system plays a more active role in coarctation than previously believed.

Pathogenesis of paradoxical hypertension after coarctation resection.

The pathogenesis of paradoxical hypertension after resection of coarctation of the aorta was investigated by comparing the course of seven children undergoing repair of coarctation with five acyanotic children undergoing elective cardiovascular surgery. During the first 24 hours after surgery, all coarctation patients demonstrated a rise in systolic blood pressure (35 +/- 15.5 mm Hg; P less than 0.001), a significant depression in cold pressor test response, and only a slight elevation in plasma renin activity. In the next 24-72 hours, coarctation patients developed a rise in diastolic blood pressure (26.8 +/- 10.6 mm Hg; P less than 0.001), plasma renin activity (22.9 +/- 10.2/ml/hr; P less than 0.001) and fluid retention. By contrast, control patients had no significant postoperative changes. Abdominal pain occurred in five coarctation patients during the period of maximal plasma renin activity. The data suggest that the sympathetic nervous system may be responsible for the initial phase of hypertension after coarctation resection and that the renin angiotension system plays a major role in the second phase of hypertension and in the pathogenesis of mesenteric arteritis.

Acute post-traumatic coarctation of the abdominal aorta.

An unusual case of coarctation of the abdominal aorta following trauma in reported. The resultant supratenal aortic constriction was associated with severe hypertension and elevated plasma renin concentration. Gradual aortic dilation at the suture site was accompanied by remission of hypertension and return of plasma renin concentration to normal. Correlation of laboratory and hemodynamic changes resulting from this unusual case of abdominal coarctation is discussed.

Plasms renin acitivity in coarctation of aorta before and after surgery.

Plasma renin acitivity was measured in II cases of coarctation of the aorta before and after operation. The values of plasma renin activity in the recumbent position before operation were significantly lower than in the control group. After surgery plasma renin activity rose to normal levels. There was no correlation between plasma renin activity levels and arterial blood pressure. The renin-angiotensin system seems not to be involved directly in the maintenance of hypertension in patients with aortic coarctation.