Life and Death: A Multicenter Study Evaluating Cardiologists' Approach to Difficult Conversations with Fontan Patients and Families.

Outpatient cardiologists provide longitudinal care for Fontan patients. As these patients age, they face mounting morbidities, necessitating challenging conversations about prognosis and goals of care. We created a novel survey to evaluate cardiologists' attitudes surrounding risk counseling for patients/caregivers. Cardiologists were recruited during concomitant outpatient enrollment of individuals with Fontan operation > age 10. Physician demographic data, expectations of timing in discussing adverse event risk, and perceived barriers were collected. Barriers were analyzed using a thematic approach. 40 cardiologists (9 institutions) responded regarding 155 patients (mean age 21.2 years, SD 7.7). Physicians were mostly male (58%) with mean practice of 21 years post-fellowship (SD 12). Most felt the time was right to have a conversation with patient (55%) and family (62%), and majority thought patient (53%) and family (75%) were ready for such a conversation. Most had previously discussed prognosis with patient (72%) and family (75%). Providers were inclined to discuss risk with caregivers earlier (mean patient age 9 years, SD 11) than patients (mean patient age 17 years, SD 6.4). Nevertheless, 42% of physicians perceived significant barriers and provided 58 narrative comments categorized into 4 major themes: (1) Patient-related (53.4%), including cognitive limitations and mental health; (2) Provider-related (16.4%), including lack of familiarity, preservation of happiness, and discomfort; (3) Family related (12.3%), including protection/denial and psychosocial stressors; (4) Other (26%), including social barriers. Experienced cardiologists are willing to have difficult conversations; nearly half reported largely patient-related barriers. Facilitating these conversations is critical for the adolescent/young adult with Fontan physiology.

How Good Are Cardiologists at Predicting Major Adverse Events in Fontan Patients?

Background: It is unknown how well cardiologists predict which Fontan patients are at risk for major adverse events (MAEs). Objectives: The purpose of this study was to examine the accuracy of cardiologists' ability to identify the "good Fontan" patient, free from MAE within the following year, and compare that predicted risk cohort to patients who experienced MAE. Methods: This prospective, multicenter study included patients ≥10 years with lateral tunnel or extracardiac Fontan. The cardiologist was asked the yes/no "surprise" question: would you be surprised if your patient has a MAE in the next year? After 12 months, the cardiologist was surveyed to assess MAE. Agreement between cardiologist predictions of MAE and observed MAE was determined using the simple kappa coefficient. Multivariable generalized linear mixed effects models were performed to identify factors associated with MAE. Results: Overall, 146 patients were enrolled, and 99/146 (68%) patients w`ere predicted to be a "good Fontan." After 12 months, 17 (12%) experienced a MAE. The simple kappa coefficient of cardiologists' prediction was 0.17 (95% CI: 0.02-0.32), suggesting prediction of MAE was 17% better than random chance. In the multivariable cardiologist-predicted MAE (N = 47) model, diuretic/beta-blocker use (P ≤ 0.001) and systolic dysfunction (P = 0.005) were associated with MAE. In the observed multivariable MAE (N = 17) model, prior unplanned cardiac admission (P = 0.006), diuretic/beta-blocker use (P = 0.028), and ≥moderate atrioventricular valve regurgitation (P = 0.049) were associated with MAE. Conclusions: Cardiologists are marginally able to predict which Fontan patients are at risk for MAE over a year. There was overlap between factors associated with a cardiologist's prediction of risk and observed MAE, namely the use of diuretic/beta-blocker.

Characterization of Circulating and Urinary Biomarkers in the Fontan Circulation and Their Correlation With Cardiac Imaging.

Several circulating biomarkers have been found to play a role in the surveillance and risk stratification of heart failure without congenital heart disease, but these have not been widely studied in patients with single ventricles palliated with a Fontan operation. Imaging predictors of worse outcomes in this population include ventricular dilation and dysfunction. Patients who weighed >30 kg with a Fontan circulation referred for cardiac magnetic resonance imaging were invited to participate in the study. Blood and urine samples were obtained at the time of imaging and multiple conventional and novel biomarkers were measured. A total of 82 patients with a median age of 18 years were enrolled. Among the novel biomarkers, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T had the strongest correlation with ventricular dilation and dysfunction. NT-ProBNP >100 pg/ml has a sensitivity of 91% for the detection of significant ventricular dilation (end-diastolic volume >120 ml/body surface area1.3) and 82% for detection of ejection fraction <50%. The urinary neutrophil gelatinase-associated lipocalin-2 to creatinine ratio correlated with ejection fraction and estimated glomerular filteration rate. In conclusion, abnormalities in biomarkers of heart failure are common in ambulatory, largely asymptomatic patients with Fontan circulation. NT-ProBNP may serve as a sensitive marker for the identification of patients with significant ventricular dilation or dysfunction. Further work is needed to understand how these easily measured circulating biomarkers may be integrated into clinical care.

Relation of Fontan Baffle Stroke Volume to Fontan Failure and Lower Exercise Capacity in Patients With an Atriopulmonary Fontan.

Fontan failure remains a significant problem, especially in patients with an atriopulmonary Fontan. Fontan baffle volume change during the cardiac cycle (Fontan baffle stroke volume) may affect outcomes in Fontan circulation. Assuming that increased Fontan baffle stroke volume is associated with increased energy loss in the baffle, we hypothesized that higher baffle stroke volume is associated with worse exercise capacity and increased incidence of Fontan failure. Patients from 6 centers with an atriopulmonary or lateral tunnel Fontan operation were included if they had a cardiac magnetic resonance (CMR) study and an adequate cardiopulmonary exercise test. Fontan baffle stroke volume was defined as the difference between maximum and minimum Fontan baffle volumes. Fontan failure was defined as death, listing for transplantation, heart failure symptoms requiring medications, or peak VO2 below 16 ml/kg/min. The study group consisted of 107 patients (median age 19 years, interquartile range, 14 to 29 years). Most patients (84%) had lateral tunnel procedure. During a median follow-up period of 6.8 [interquartile range: 3.2 to 8.8] years after the CMR, 25 (23%) patients had Fontan failure (7 deaths, 3 listed for transplantation, and 15 with heart failure symptoms). Predictors of Fontan failure on multivariable analysis were ventricular tachycardia, protein losing enteropathy, and additionally in atriopulmonary Fontan only, larger Fontan baffle stroke volume. Predictors of lower peak VO2 on multivariable analysis were older age at CMR and additionally in atriopulmonary Fontan only, larger Fontan baffle stroke volume. In conclusion, larger Fontan baffle stroke volume was independently associated with lower peak VO2 and Fontan failure in atriopulmonary Fontan.

Maldistribution of pulmonary blood flow in patients after the Fontan operation is associated with worse exercise capacity.

BACKGROUND: Maldistribution of pulmonary artery blood flow (MPBF) is a potential complication in patients who have undergone single ventricle palliation culminating in the Fontan procedure. Cardiovascular magnetic resonance (CMR) is the best modality that can evaluate MPBF in this population. The purpose of this study is to identify the prevalence and associations of MPBF and to determine the impact of MPBF on exercise capacity after the Fontan operation. METHODS: This retrospective single-center study included all patients after Fontan operation who had maximal cardiopulmonary exercise test (CPET) and CMR with flow measurements of the branch pulmonary arteries. MPBF was defined as > 20% difference in branch pulmonary artery flow. Exercise capacity was measured as percent of predicted oxygen consumption at peak exercise (% predicted VO2). Linear and logistic regression models were used to determine univariate and multivariable predictors of exercise capacity and correlates of MPBF, respectively. RESULTS: A total of 147 patients who had CMR between 1999 and 2017 were included (median age at CMR 21.8 years [interquartile range (IQR) 16.5-30.6]) and the median time between CMR and CPET was 2.8 months [IQR 0-13.8]. Fifty-three patients (36%) had MPBF (95% CI 29-45%). The mean % predicted VO2 was 63 ± 16%. Patients with MPBF had lower mean % predicted VO2 compared to patients without MPBF (60 ± 14% versus 65 ± 16%, p = 0.04). On multivariable analysis, a lower % predicted VO2 was independently associated with longer time since Fontan, higher ventricular mass-to-volume ratio, and MPBF. On multivariable analysis, only compression of the branch pulmonary arteries by the ascending aorta or aortic root was associated with MPBF (OR 6.5, 95% CI 5.6-7.4, p < 0.001). CONCLUSION: In patients after the Fontan operation, MPBF is common and is independently associated with lower exercise capacity. MPBF was most likely to be caused by pulmonary artery compression by the aortic root or the ascending aorta. This study identifies MPBF as an important risk factor and as a potential target for therapeutic interventions in this fragile patient population.

Impact of Ventricular Morphology on Fiber Stress and Strain in Fontan Patients.

BACKGROUND: Right ventricular (RV) morphology has been associated with adverse clinical outcomes in Fontan patients. The impact of RV versus left ventricular morphology on ventricular stress and strain in single ventricles is not well known. METHODS AND RESULTS: Cardiac magnetic resonance examinations in 193 patients with the Fontan circulation were retrospectively analyzed. Ventricular mass, volume, global circumferential and longitudinal strain, and global average end-systolic fiber stress were calculated using previously published methods. Compared with left ventricular morphology, RV morphology (48%) was associated with higher ventricular end-diastolic volume (110 mL/BSA1.3 versus 84 mL/BSA1.3, P<0.001), lower mass-to-volume ratio (0.46 versus 0.57, P<0.001), higher global average end-systolic fiber stress (23 kPa versus 20 kPa, P=0.002), worse global circumferential strain (-21% versus -24%, P<0.001), and higher prevalence of greater than or equal to moderate atrioventricular valve regurgitation (25% versus 6%, P<0.001). Ejection fraction and global longitudinal strain were similar between the groups. Death or listing for heart transplantation occurred in 24 (12%) with a median follow-up of 6.2 years. On univariate analysis, RV morphology, ventricular dilatation, and worse global circumferential strain were associated with this composite outcome. CONCLUSIONS: In comparison to Fontan patients with a dominant left ventricle, those with a dominant RV have higher fiber stress, a higher rate of ventricular dilatation, lower circumferential fiber shortening, and similar longitudinal shortening. RV morphology, ventricular dilation, and worse circumferential strain are associated with death or heart transplantation. The difference in myofiber architecture may contribute to suboptimal adaptation of the RV as a systemic ventricle.

Measurement of neosaxitoxin in human plasma using liquid-chromatography tandem mass spectrometry: Proof of concept for a pharmacokinetic application.

Neosaxitoxin, a member of the saxitoxin family of paralytic shellfish poisoning toxins, has shown potential as an effective, long-acting, anesthetic. We describe the development and validation of a highly sensitive method for measurement of neosaxitoxin in human plasma using liquid chromatography tandem mass spectrometry (LC-MS/MS) and provide evidence for its use in a human pharmacokinetic study. Samples were prepared using cation exchange solid phase extraction followed by hydrophilic interaction liquid chromatography and MS/MS detection in positive electrospray ionization mode. Multiple reaction monitoring was used to monitor neosaxitoxin (m/z 316.17>220.07) and the internal standard analogue decarbamoylneosaxitoxin (m/z 273.12>180.00). The method was validated for lower limit of quantification, precision, accuracy, linearity and matrix effect. The stability of neosaxitoxin in plasma matrix at various storage conditions was also investigated. Standard curves for calibration were linear (r>0.995) across the assay calibration range, 10 to 1000pg/mL. The analytical measurable range of the assay was 10-10,000pg/mL in plasma matrix. This method has demonstrated excellent sensitivity demonstrating a lower limit of quantification in human plasma of 10pg/mL. The mean, inter-batch variation was <5.2% across the concentration range 30 to 800pg/mL. This method was successfully used in a phase 1 trial to investigate the pharmacokinetic profile of neosaxitoxin in humans following the intravenous administration of the drug at a range of doses up to 40µg. We conclude that our high-sensitivity method for measurement of neosaxitoxin in human plasma is capable of supporting future clinical trials.