Endothelial function following the Fontan operation.

O for children with most forms of congenital heart disease continue to improve. Nonetheless, long-term morbidity—such as progressive ventricular dysfunction and congestive heart failure—for patients with single ventricular lesions remains high.1 The factors that contribute to hemodynamic compromise are incompletely understood. Although abnormal mechanics of the single ventricle have been well documented, recent evidence suggests that there may be a complex interplay between the heart and the peripheral and pulmonary vasculature in patients after the Fontan operation.2,3 In adults with congestive heart failure, endothelial dysfunction is common.4 Perturbations of the nitric oxide pathway are believed to play a critical role in endothelial dysfunction in these patients, and therapies directed at enhancing nitric oxide production have been proposed.5,6 Several previous studies have suggested that the nitric oxide pathway is also abnormal in patients after the Fontan procedure.3,7 These findings have particular importance because improving the endothelial response in Fontan patients has the potential to reduce of the risk of developing congestive heart failure. In the present study, we studied the endothelial function in a group of asymptomatic patients who underwent the Fontan operation. In addition, we examined factors that influence endothelial function, including abnormalities of the nitric oxide pathway. • • • We assessed endothelial function in nonselected subjects with single ventricular anatomy after the Fontan procedure and in subjects with normal cardiac anatomy (controls). Patients who presented for routine outpatient evaluation between January and September 2002 were eligible for enrollment. The single-ventricle cohort was comprised of patients who underwent the Fontan procedure and were 6 years of age. All subjects were evaluated for functional status as previously applied in pediatric populations.1 Subjects in New York Heart Association (NYHA) classes III or IV were excluded from study. Control patients (n 19) were obtained from children referred for electrocardiography or echocardiography who had no evidence of heart disease by physical examination and/or echocardiography. Patients with chronic illness, such as diabetes mellitus or a family history of hyperlipidemia or premature coronary artery disease, were excluded. Twenty-three patients with single-ventricle lesions were entered into the study. Mean age was 11.8 4.2 years. The most common diagnosis was hypoplastic left heart syndrome, which was present in 10 patients (43%). Prior aortic arch surgery for coarctation or arch hypoplasia had been performed in 13 patients (57%). Fifteen of the patients (65%) were receiving an angiotensin-converting enzyme (ACE) inhibitor. ACE inhibitors included captopril (n 5), enalopril (n 3), and lisinopril (n 7). Fourteen subjects (61%) were in NYHA class I and 9 (39%) were in class II. Thirteen patients (57%) had undergone pacemaker implantation for sinus node dysfunction. Endothelial function of the brachial artery was assessed by means of high-resolution ultrasound, diameter changes in response to reactive hyperemia, and flow-mediated vasodilation (FMD), according to the standard protocols.8 The brachial artery was examined by 2-dimensional ultrasound images, with a 10-MHz linear array transducer and a standard Sonos 5500system (Philips, Andover, Massachusetts). The subjects lay at rest for 5 minutes before beginning the scan for endothelial function. A scan at rest was recorded for 1 minute. A pneumatic tourniquet, placed at the subject’s forearm, was then inflated to a pressure of 180 mm Hg for 4.5 minutes. The vessel was continuously scanned during the procedure, from baseline until 3 minutes after release of the cuff. Studies were reviewed by an independent reviewer (DAF) who was blinded to each patient’s clinical status. The arterial diameter was measured at enddiastole in triplicate at rest and at maximal dilation 60 to 90 seconds after cuff deflation. In those patients who underwent a prior modified Blalock-Taussig shunt, endothelial function was assessed in the contralateral arm. Plasma concentrations of L-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were measured by highperformance liquid chromatography as previously described.9 Blood samples for Fontan patients were obtained within 90 minutes of brachial artery assessment. Samples were processed at Oxononus (Emeryville, California). Statistical analysis was performed with the STATA (STATA, College Station, Texas) software, version 6.0 for IBM-PC. Descriptive data are expressed as mean SD. Quantitative data were correlated using regression analysis, calculating the coefficient of correlation R. To compare quantitative data of the 2 groups, the Mann-Whitney U test was applied. There were no significant differences between single ventricle patients and controls with respect to age, heart rate, blood pressure, or weight (Table 1). The median FMD was significantly less in the singleventricle patients than in controls (median 4.2% vs 7.9%) (Figure 1). In univariate analysis, there was a trend toward higher FMD in those Fontan patients receiving an ACE inhibitor compared with those not From Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia. Dr. Mahle’s address is: Sibley Heart Center Cardiology, Children’s Healthcare of Atlanta, 52 Executive Park South, Suite 5200, Atlanta, Georgia 30329. E-mail: wmahle@emory.edu. Manuscript received December 10, 2002; revised manuscript received and accepted February 10, 2003.