Orthostatic stress response in pediatric Fontan patients and the effect of ACE inhibition.

BACKGROUND: Many cardiocirculatory mechanisms are involved in the adaptation to orthostatic stress. While these mechanisms may be impaired in Fontan patients. However, it is yet unclear how Fontan patients, who exhibit a critical fluid balance, respond to orthostatic stress. Angiotensin converting enzyme inhibitors are often prescribed to Fontan patients, but they may negatively influence orthostatic tolerance. Therefore, we evaluated the response to orthostatic stress in pediatric Fontan patients before and after treatment with enalapril. METHODS: Thirty-five Fontan patients (aged 14 years) with moderate-good systolic ventricular function without pre-existent enalapril treatment were included. Before and after a three-month enalapril treatment period, the hemodynamic response to head-up tilt test was evaluated by various parameters including cardiac index, blood pressure, cerebral blood flow, aortic stiffness and cardiac autonomous nervous activity. Thirty-four healthy subjects (aged 13 years) served as controls. RESULTS: Fontan patients had a decreased cerebral blood flow and increased aortic stiffness in the supine position compared to controls, while all other factors did not differ. Patients and controls showed a comparable response to head-up tilt test for most parameters. Twenty-seven patients completed the enalapril study with a mean dosage of 0.3±0.1mg/kg/day. Most parameters were unaffected by enalapril, only the percent decrease in cardiac index to tilt was higher after treatment, but the cardiac index during tilt was not lower (3.0L/min/m2 pre-enalapril versus 2.8L/min/m2 after treatment; P = 0.15). CONCLUSION: Pediatric Fontan patients adequately respond to orthostasis with maintenance of blood pressure and cerebral blood flow and sufficient autonomic response. Enalapril treatment did not alter the response. CLINICAL TRIAL INFORMATION: Scientific title: ACE inhibition in Fontan patients: its effect on body fluid regulation (sAFE-study). The Netherlands National Trial Register: Trail NL6415. Registered 2017-07-20. Trial information: https://www.trialregister.nl/trial/6415.

3-Month Enalapril Treatment in Pediatric Fontan Patients With Moderate to Good Systolic Ventricular Function.

Many Fontan patients with and without systolic ventricular dysfunction are being treated with angiotensin-converting enzyme (ACE) inhibitors, despite its effectiveness remaining unclear. In the present study, we evaluated the short-term effect of enalapril on exercise capacity, vascular and ventricular function in pediatric Fontan patients with moderate-good systolic ventricular function. Fontan patients between 8 and 18 years with moderate-good systolic ventricular function and without previous ACE inhibitor treatment were included and were treated with enalapril for 3 months. During the first 2 weeks, the dosage was titrated according to systolic blood pressure (SBP). Exercise tests, ventricular function assessed by echocardiography, arterial stiffness measurements, and plasma levels of N-terminal pro-B-type natriuretic peptide assessed before and after a 3-month enalapril treatment period was compared. A total of 28 Fontan patients (median age 13.9 years, 6 to 15 years after Fontan operation) completed the study with a mean dosage of 0.3 ± 0.1 mg/kg/d. A total of 6 patients (21%) experienced a significant drop in SBP and 6 others (21%) experienced other adverse events. Enalapril treatment lowered the SBP (from 110 to 104 mmHg, p = 0.003) and levels of N-terminal pro-B-type natriuretic peptide (from 80 to 72 ng/L, p = 0.036). However, enalapril treatment did not improve exercise capacity, ventricular function, or arterial stiffness. In conclusion, short-term ACE inhibition has no beneficial effect in Fontan patients with moderate-good systolic ventricular function.

Determinants of exercise limitation in contemporary paediatric Fontan patients with an extra cardiac conduit.

BACKGROUND: Although various determinants of exercise limitation in Fontan patients have been studied, most research has been performed in patients who underwent different surgical procedures with differing haemodynamic characteristics. The aim of the current study was to evaluate non-invasively measured cardiovascular parameters and their influence on exercise performance in paediatric Fontan patients with an extracardiac conduit and moderate-good systolic ventricular function. METHODS: Fontan patients, between 8 and 18 years of age, with moderate to good systolic ventricular function and an extracardiac conduit were included. Exercise performance and cardiovascular assessment, comprising echocardiography, aortic stiffness measurement and ambulatory measurement of cardiac autonomous nervous activity were performed on the same day. Healthy subjects served as controls. RESULTS: Thirty-six Fontan patients (age 14.0 years) and thirty-five healthy subjects (age 12.8 years) were included. Compared to controls, Fontan patients had reduced diastolic ventricular function and increased arterial stiffness. No differences were found in heart rate (HR) and cardiac parasympathetic nervous activity. In Fontan patients, maximal as well as submaximal exercise capacity was impaired, with the percentage of predicted capacity ranging between 54 and 72%. Chronotropic competence, however, was good with a peak HR of 174 (94% of predicted). Lower maximal and submaximal exercise capacity was correlated with a higher HR at rest, higher pulse wave velocity of the aorta and a lower ratio of early and late diastolic flow velocity. CONCLUSION: Contemporary paediatric Fontan patients have an impaired exercise capacity with preserved chronotropic competence. Exercise performance correlates with heart rate at rest, diastolic function and aortic stiffness.

Prognostic Value of Maximal and Submaximal Exercise Performance in Fontan Patients < 15 Years of Age.

In patients after Fontan completion exercise capacity is significantly reduced. Although peak oxygen consumption (VO2peak) is a strong prognostic factor in many cardiovascular diseases, it requires the achievement of a maximal effort. Therefore, submaximal exercise parameters such as oxygen uptake efficiency slope (OUES) may be of value. In the present observational study we evaluated the exercise capacity with maximal and submaximal parameters in a group of Fontan patients with an extracardiac conduit and determined their prognostic value. Sixty Fontan patients followed up in the Leiden University Medical Center who have performed an exercise test were included in this retrospective study. Exercise tests were performed at a median age of 11 years. Fontan patients showed on average lower values for all exercise parameters compared to reference values from a healthy dataset as shown by the %predicted values: VO2peak%:mean 66%(95%CI:64 to 74) and OUES%:mean 72%(95%CI:67 to 77). Twenty percent of the patients were not able to achieve an RER>1.0. RER showed a moderate positive correlation with VO2peak but not with OUES. There was a deterioration of VO2peak% and OUES% over time. OUES was significantly lower in patients with cardiac events in the follow up period. Fontan patients have an impaired exercise performance even at young ages and it deteriorates with age. An important percentage of Fontan patients is not able to reach maximal effort so the use of submaximal parameters, like OUES, should be considered as part of the evaluation. Moreover, OUES could have a prognostic value in this group of patients.

Maturation of the Cardiac Autonomic Nervous System Activity in Children and Adolescents.

Background Despite the increasing interest in cardiac autonomic nervous activity, the normal development is not fully understood. The main aim was to determine the maturation of different cardiac sympathetic-(SNS) and parasympathetic nervous system (PNS) activity parameters in healthy patients aged 0.5 to 20 years. A second aim was to determine potential sex differences. Methods and Results Five studies covering the 0.5- to 20-year age range provided impedance- and electrocardiography recordings from which heart rate, different PNS-parameters (eg, respiratory sinus arrhythmia) and an SNS-parameter (pre-ejection period) were collected. Age trends were computed in the mean values across 12 age-bins and in the age-specific variances. Age was associated with changes in mean and variance of all parameters. PNS-activity followed a cubic trend, with an exponential increase from infancy, a plateau phase during middle childhood, followed by a decrease to adolescence. SNS-activity showed a more linear trend, with a gradual decrease from infancy to adolescence. Boys had higher SNS-activity at ages 11 to 15 years, while PNS-activity was higher at 5 and 11 to 12 years with the plateau level reached earlier in girls. Interindividual variation was high at all ages. Variance was reasonably stable for SNS- and the log-transformed PNS-parameters. Conclusions Cardiac PNS- and SNS-activity in childhood follows different maturational trajectories. Whereas PNS-activity shows a cubic trend with a plateau phase during middle childhood, SNS-activity shows a linear decrease from 0.5 to 20 years. Despite the large samples used, clinical use of the sex-specific centile and percentile normative values is modest in view of the large individual differences, even within narrow age bands.

Treatment and outcome of plastic bronchitis in single ventricle patients: a systematic review.

Plastic bronchitis (PB) is a life-threatening complication in single ventricle (SV) patients of which the exact pathophysiology, outcome and optimal treatment are still unclear. This study aims to systematically review the literature to give insight into the characteristics, outcome and management options of SV patients with PB. A systematic review was conducted, using the electronic database PubMed to find records published up to August 2018, describing SV patients and PB in which characteristics, treatment and/or outcome were adequately described per case. A total of 577 records were screened of which 73 had sufficient data describing 133 SV cases with PB. Most cases had completed a Fontan palliation (n = 126) with a median interval between Fontan completion and diagnosis of PB of 18.4 months (Q1-Q3 5.0-36.3). Overall mortality was 15.2% and was associated with the diagnosis of PB within 12 months after Fontan palliation (5-year survival of 56.1% ≤12 months vs 94.8% >12 months, P = 0.002) and a higher age at Fontan completion (47.4 months for non-survivors vs 36.0 months for survivors, P = 0.015). Most patients received a combination therapy from 3 different treatment strategies, i.e. therapy for relief of airway obstruction, anti-inflammatory treatment and treatment to improve haemodynamics of the Fontan physiology (55.1%). In conclusion, SV patients who are diagnosed with PB within 12 months after Fontan palliation have a higher risk of mortality. Moreover, most cases received a combination therapy consisting of all 3 treatment strategies.