Large Right Atrial Size on Cardiac MRI is Associated with Post-operative Right Ventricular Dysfunction After the Cone Operation for Ebstein Anomaly.

The cone operation has revolutionized care for patients with Ebstein anomaly; however, acute post-operative right ventricular dysfunction (RVD) is common in this patient population. A single-center, retrospective review of 28 patients with Ebstein anomaly who underwent cardiac MRI (CMR) prior to cone reconstruction of the tricuspid valve was conducted. Measurements of atrial and ventricular size/function were assessed. Post-operative RVD was defined as the presence of moderate or severe systolic dysfunction on discharge echo. A two-tail t test was employed to compare the two groups. The average age at operation was 21.4 years (range 1.6-57.8) and 14 (50%) had RVD at discharge. Patients with post-operative RVD had significantly larger pre-operative right atrial (RA) maximum volume (p = 0.016) and RA minimum volume (p = 0.030). Patients with RVD had smaller pre-operative left atrial (LA) minimum volume (p = 0.012). Larger pre-operative right ventricular (RV) end-systolic volume (p = 0.046), lower RV ejection fraction (0.029), and smaller left ventricular (LV) end-diastolic volume (p = 0.049) were significantly associated with post-operative RVD. Post-operative RVD was associated with longer milrinone duration (p = 0.009) and higher maximum milrinone dose (p = 0.005) but was not associated with intensive care or hospital length of stay (p = 0.19 and 0.67, respectively). Increased RA and RV dilation and decreased LA and LV volumes are associated with the development of post-operative RVD following cone operation for Ebstein anomaly. Post-operative RVD affects milrinone dose and duration but is not associated with increased length of stay.

From Other Journals: A Review of Recent Articles by Our Editorial Team.

In this review we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. Our hope is to provide a summary of the latest articles published recently in other journals in our field. The articles address: 1- The use of AI in fetal echocardiography, 2- The role of Apixaban in thromboembolism prevention in pediatric congenital heart disease, 3- Cardiovascular events in childhood cancer survivors, and lastly 4- the new consensus statement on cardiac catheterization for pediatrics and adults with congenital heart disease.

Impact of guideline directed medical therapy on myocardial function in adults with congenital heart disease.

BACKGROUND: Guideline-directed heart failure therapy with angiotensin receptor blocker/neprilysin inhibitor (ARNi) and sodium-glucose transporter inhibitors (SGLT2i) has been incrementally beneficial in improving outcomes in heart failure patients. OBJECTIVE: Evaluate the feasibility and efficacy of guideline-directed medical therapy (GDMT) in adults congenital heart disease (ACHD) patients. METHODS: In a retrospective cohort study, ACHD patients with either New York Heart Association (NYHA) Class II symptoms or systemic ejection fraction (EF) <45%, optimized on a combination of beta-blocker (BB), ARNi, mineralocorticoid receptor antagonist (MRA) and SGLT2i were evaluated. RESULTS: Forty-six patients with a mean age 42.6 ± 12.1 years prescribed GDMT were identified. Twenty-eight (61%) were male, 20 (43%) had a systemic right ventricle (RV) and 9 (20%) had single-ventricle physiology. Over the optimization period, 20 (43%) were sustained on ARNi and 42 (91%) on SGLT2i in addition to treatment with BB and MRA. Over a period of 45 weeks, echocardiography parameters for left ventricle (LV) ejection fraction (EF) (+7.5%, p = 0.006), systemic ventricle (SV) velocity time integral (VTI) (+1.9 cm, p = 0.012) and LV global longitudinal strain (GLS) (-2.5%, p = 0.005) improved when 3-4 medications were used versus 1-2 medications alone. The use of either ARNi or SGLT2i (+8.1%, p = 0.017) or in combination (+7.0%, p = 0.043) increased LVEF compared to the use of neither medication. CONCLUSION: Combination GDMT is beneficial in improving myocardial characteristics in ACHD patients with systemic RV and LV.

Assessing Left Ventricular Pathology in Patients with Ebstein Anomaly Using Cardiovascular Magnetic Resonance: Looking Past the Right Heart.

Ebstein Anomaly (EA) is a malformation of the right heart, but there is data to suggest that the left ventricle (LV) can suffer from intrinsic structural and functional abnormalities which affect surgical outcomes. The LV in patients with EA is hypertrabeculated with abnormalities in LV function and strain. In this retrospective single-center study, patients with EA who underwent pre-operative cardiac MRI (CMR) between the periods of 2014-2024 were included along with a group of healthy-age-matched controls. Left ventricular and right ventricular volume, function and strain analyses were performed on standard SSFP imaging. LV noncompacted: compacted (NC/C) ratio and the displacement index of the tricuspid valve were measured. Forty-seven EA patients were included with mean age of 21.0 ± 17.6 years. Seventeen EA patients (36%) had mild pre-operative LV dysfunction on CMR and 1 (2.1%) had moderate LV dysfunction. Out of these 18 patients with LV dysfunction, only 2 were detected to have dysfunction on Echocardiogram. The global circumferential and longitudinal strain were significantly lower in the reduced LVEF group compared to those with preserved LVEF (- 14.8% vs. - 17%, p = 0.02 and - 11.9% vs. - 15.0%; p = 0.05; respectively) on CMR. A single EA patient met criteria for LVNC with a maximal NC/C ratio > 2.3. There was no statistically significant difference in NC/C ratio in the EA population (1.4 ± 0.6) vs. controls (1.1 ± 0.2), p = 0.17. There was an inverse correlation of LV ejection fraction with right ventricular end-diastolic volume and displacement index. All patients underwent the Da Silva Cone procedure at our center. Patients with preoperative LV dysfunction had longer duration of epinephrine use in the immediate postoperative period (33.7 ± 21.4 vs 10.2 ± 25.6 h, p = 0.02) and longer length of hospital stay (6.3 ± 3.2 vs 4.4 ± 1.2 days, p = 0.01). This is the largest study to date to evaluate preoperative LV structure and function in EA patients by CMR. In this cohort of 47 patients, preoperative LV dysfunction is fairly common and CMR has high sensitivity in detecting LV dysfunction as compared to Echo. True LV non-compaction was rare in this cohort. The presence of LV dysfunction is relevant to perioperative management and further study with larger cohorts and longer follow up are necessary.

Thrombocytopenia is Associated with Higher Fontan Pressure and Increased Morbidity in Patients with Fontan Circulation.

After the Fontan procedure, patients require lifelong follow-up due to significant late morbidity and mortality. Thrombocytopenia is seen frequently post-Fontan, likely due to secondary hypersplenism from elevated Fontan pressure. We investigated platelet counts in patients with a Fontan circulation and assessed associations with catheterization data and clinical outcomes. This retrospective study included 92 patients (33% female) post-Fontan who had a complete blood count performed between January 2011 and July 2023. The age at evaluation was 24.0 ± 8.9 years. Outcomes measured included elevated Fontan pressure (≥ 15 mmHg), Fontan-associated liver disease (FALD), unscheduled admissions, transplant, and death. Participants with thrombocytopenia (≤ 150,000/µL) had significantly higher rates of elevated Fontan pressure (OR 8.1, 95% CI 1.3-52.7, p = 0.03), FALD (OR 4.1, 95% CI 1.6-10.6, p = 0.004), and unscheduled admissions (362 ± 577 versus 115 ± 185 admissions per 1000 patient-years, p = 0.02). Thrombocytopenia post-Fontan is associated with elevated Fontan pressure, FALD, and increased morbidity. Platelet count could serve as a non-invasive factor in identifying patients at risk of decompensation.

T1 mapping: a non-invasive tool to assess the systemic right ventricle.

Ventricular remodeling leads to fibrotic changes in systemic right ventricles (RV). Native T1 mapping provides a quantitative measure in myocardial tissue characterization. The aim of our study was to correlate native T1 values of the systemic RV to function and volumetric data. Native T1 maps were generated with a single breath hold Modified Look-Locker Inversion-recovery pulse (MOLLI) sequence was acquired in the mid-ventricular short axis. Regions of interest (ROI) were drawn in both ventricular free walls, the interventricular septum (IVS), superior insertion point (SIP) and inferior insertion point (IIP) to obtain native T1 values. T1 values were compared to CMR ventricular volumes and function using Spearman correlation. The median age was 36 years (IQR 27-48 years). There were elevated mean native left ventricular (LV) T1 and IIP T1 values at 1122 ± 171 ms and 1117 ± 96 ms, respectively. RV dysfunction was associated with elevated IIP T1 (p = 0.007). Significant moderate negative correlations were seen between RV T1 and LV ejection fraction (LVEF) (r= -0.63, p = 0.01), between RV: IVS T1 ratio and LVEF (r= -0.68, p = 0.006), between LVEF and SIP: IVS T1 ratios (r= -0.54, p = 0.04), and RVEF and IIP T1 (r= -0.59, p = 0.02). Fibrosis measured by native T1 mapping in the systemic RV is most prominent in the LV wall and septal insertion point and correlates with decreased function. T1 values can be used in non-invasive imaging assessment of the RV, but further studies with larger cohorts are needed to assess ability to risk stratify and guide therapy.

Augmented Biphasic Breathing Using Sniff and an Oral Positive Expiratory Pressure Device (Sniff-PEP) in Fontan Patients.

The use of an oral positive expiratory pressure device (oPEP) with sniff breathing (Sniff-PEP) mimics biphasic ventilation. Biphasic ventilation increases pulmonary blood flow and cardiac output in Fontan patients. The aim of this study was to assess the effect of Sniff-PEP on Fontan flow velocities. A single-center, pilot, prospective study was carried out in 15 subjects with Fontan circulation enrolled to use the oPEP device for 1 month. Subjects were instructed on Sniff-PEP and to use the device for 10-15 min 3-4 times a day. Measurements of flow velocity and cardiac output were measured via echocardiogram and quality of life assessments were performed at baseline and 4-6 weeks later. The mean age at enrollment was 19.9 ± 8.7 years (age range of 10-37 years). 7 patients (47%) had dominant left ventricle and 8 (53%) had an open fenestration. There was a statistically significant increase in flow velocities in the hepatic vein from 27.5 ± 7.6 to 35.1 ± 11.3 cm/s (p = 0.003), left pulmonary artery from 51.6 ± 16.6 to 57.6 ± 21.1 cm/s (p = 0.01), and right pulmonary artery from 43.1 ± 14.2 to 45.8 ± 17.2 cm/s (p = 0.04). With chronic use, the mean fenestration gradient slightly decreased from 4.5 ± 1.6 to 4.1 ± 1.9 mmHg but the difference was not statistically significant (p = 0.14). oPEP device therapy increased flow velocity in several areas in the Fontan circulation with acute use. Further studies are needed to assess the effects long term.Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT03251742.

Participation in Competitive Sports by Patients With Congenital Heart Disease: AHA/ACC and EAPC/ESC/AEPC Guidelines Comparison.

Sports participation in patients with congenital heart disease is an evolving subject. The American Heart Association/American College of Cardiology released a set of guidelines that advise the type and level of sports participation based primarily on anatomical defects with secondary consideration given to hemodynamic effects. Recently, the European Association of Preventive Cardiology/European Society of Cardiology/Association for European Paediatric and Congenital Cardiology offered a contrasting approach to sports participation that is based on hemodynamic and electrophysiological profiles of each patient, regardless of anatomical consideration. These guidelines are drastically different in their approaches but do have some similarities. In this review, we compare both documents, focusing on the aim, population, classification of sports, and the methodology of making recommendations. This review aims to assist practicing cardiologists in integrating the available published data and recommendations when counseling patients for sports participation.

Prenatal Predictors for Pulmonary Balloon Valvuloplasty in the Newborn.

Pulmonary balloon valvuloplasty (PBV) is the treatment of choice for subjects with isolated pulmonary valve stenosis (IPS). The purpose of this study was to define fetal echocardiographic features associated with an inpatient PBV prior to newborn hospital discharge and characterize resource utilization of IPS fetuses among participating centers. Six center, retrospective case series of singleton fetuses identified between 2010 and 2020 with IPS. Third-trimester echocardiogram data was compared with postnatal data, included pulmonary valve Doppler velocities, pulmonary valve insufficiency and ductus arteriosus flow direction. Comparison between subjects who underwent inpatient PBV during their newborn hospital admission versus those infants referred for outpatient PBV after initial hospital discharge. We analyzed data by logistic regression, student t test and Chi-Square testing with a p value of ≤ 0.05 considered statistically significant. Forty-nine IPS fetuses were identified. Thirty-eight (78%) underwent inpatient PBV at 5 (range 1-58) days and 11 (22%) underwent outpatient PBV at 51.8 (11-174) days. Newborns requiring an inpatient PBV were more likely to have one or more characteristics on 3rd-trimester fetal echocardiogram: left to right or bidirectional ductus arteriosus flow (61% vs 0%), and/or a peak pulmonary valve velocity > 3.0 m/s (odds ratio 16.9, 95% confidence interval 3.02-94.17) with a sensitivity of 90.4% and specificity of 97.7%. Ductus arteriosus flow direction and pulmonary valve peak velocity in the 3rd trimester can successfully predict the need for newborn inpatient PBV. We speculate these findings may be useful in choosing delivery site for the pregnancy complicated by fetal IPS.

From Other Journals: A Review of Recent Articles by Our Editorial Team.

In this review, we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. Our hope is to provide a summary of the latest articles published recently in other journals in our field. The articles address (1) A new index for prenatal diagnosis of total anomalous pulmonary venous return, (2) Outcomes of patients with Tetralogy of Fallot after pulmonary valve replacement (PVR), and (3) Short-term outcomes of the self expanding Harmony valve for transcatheter PVR.

Right Atrial Enlargement on Electrocardiogram in Previously Healthy Young Patients.

OBJECTIVES: To assess whether right atrial enlargement (RAE) on electrocardiogram (ECG) correlates with true RAE on echocardiogram in previously healthy young patients and to understand which patients with RAE on ECG may warrant additional testing. STUDY DESIGN: A single-center, retrospective review of previously healthy young patients with (1) ECGs that were read as RAE by a pediatric cardiologist and (2) echocardiograms obtained within 90 days of the ECG. ECGs were reviewed to confirm RAE and determine which leads met criteria. The echocardiograms were then reviewed and RA measurements with z scores obtained. A z score >2 was considered positive for RAE on echocardiogram. RESULTS: In total, 162 patients with median age 10.8 years were included in the study. A total of 23 patients had true RAE on echocardiogram, giving a positive predictive value (PPV) of 14%. In patients <1 year of age, the PPV increased to 35%. In patients older than 1 year, the PPV was low at 7%. Patients with true RAE were more likely to meet criteria for RAE in the anterior precordial leads (V1-V3) (48% vs 5%, P < .001) and meet criteria for right ventricular hypertrophy (22% vs 6%, P = .023). CONCLUSION: Our findings show that RAE on ECG has a low PPV for RAE on echocardiogram in previously healthy young patients. The highest yield for RAE on echocardiogram was observed in patients who were <1 year of age, had RAE in the anterior precordial leads, or displayed right ventricular hypertrophy on ECG.

Persistent Patent Vertical Vein After Repair of Total Anomalous Pulmonary Venous Connection (TAPVR): A Rare Cause of Hypoxemia Post-Fontan Procedure.

Vertical vein (VV) ligation during total anomalous pulmonary venous return (TAPVR) repair is controversial. While some surgeons prefer ligation of the VV to prevent adverse sequelae of shunting across it and to promote flow through the newly created anastomosis, others leave it to serve as a "pop off valve" to the left heart structures, which are believed to be hypoplastic and noncompliant, presumably contributing to a more favorable post-operative outcome. We report two patients post-Fontan procedure, who underwent cardiac catheterization to explore the etiology of hypoxia and were found to have a persistent VV responsible for right to left shunting. Both patients underwent closure of the VV with improvement in the cyanosis and clinical course. These cases provide evidence supporting surgical ligation of the VV at the time of TAPVR repair, especially in patients with single ventricle.

Double outlet right ventricle.

This review article addresses the history, morphology, anatomy, medical management, and different surgical options for patients with double outlet right ventricle.

Abnormal Global Longitudinal Strain During Anthracycline Treatment Predicts Future Cardiotoxicity in Children.

Global longitudinal strain (GLS) is a sensitive predictor of cardiotoxicity in adults with cancer. However, the significance of abnormal GLS during childhood cancer treatment is less well-understood. The objective was to evaluate the use of GLS for predicting later cardiac dysfunction in pediatric cancer survivors exposed to high-dose anthracyclines. This was a retrospective study of pediatric patients exposed to a doxorubicin isotoxic equivalent dose of ≥ 225 mg/m2. Transthoracic echocardiograms (TTE) were obtained prior to chemotherapy (T1), during anthracycline therapy (T2), and following completion of therapy (T3). Cardiotoxicity was defined as meeting at least one of the following criteria after anthracycline therapy: a decrease in left ventricle ejection fraction (LVEF) by 10% from baseline to a value < 55%, fractional shortening < 28%, or a decrease in GLS by ≥ 15% from baseline. Nineteen of 57 (33%) patients met criteria for cardiotoxicity at T3. Cardiotoxicity was associated with a lower LVEF at T2 (p = 0.0003) and a decrease in GLS by ≥ 15% at T2 compared to baseline (p = < 0.0001). ROC analysis revealed that the best predictor of cardiotoxicity at T3 was the percent change in GLS at T2 compared to baseline (AUC 0.87). A subgroup analysis revealed that a decrease in GLS by ≥ 15% from baseline at 0-6 months from completion of anthracycline therapy was associated with cardiotoxicity > 1-year post-treatment (p = 0.017). A decline in GLS during chemotherapy was the best predictor of cardiotoxicity post-treatment. GLS serves as an important marker of cardiac function in pediatric patients undergoing treatment with anthracyclines.

Long-Term outcomes in adult patients with congenital heart disease considered for transplantation: A single center study.

BACKGROUND: Adult congenital heart disease (ACHD) patients pose unique challenges in identifying the time for transplantation and factors influencing outcomes. OBJECTIVE: To identify hemodynamic, functional, and laboratory parameters that correlate with 1- and 10-year outcomes in ACHD patients considered for transplantation. METHODS: A retrospective chart review of long-term outcomes in adult patients with congenital heart disease (CHD) evaluated for heart or heart + additional organ transplant between 2004 and 2014 at our center was performed. A machine learning decision tree model was used to evaluate multiple clinical parameters correlating with 1- and 10-year survival. RESULTS: We identified 58 patients meeting criteria. D-transposition of the great arteries (D-TGA) with atrial switch operation (20.7%), tetralogy of Fallot/pulmonary atresia (15.5%), and tricuspid atresia (13.8%) were the most common diagnosis for transplant. Single ventricle patients were most likely to be listed for transplantation (39.8% of evaluated patients). Among a comprehensive list of clinical factors, invasive hemodynamic parameters (pulmonary capillary wedge pressure (PCWP), systemic vascular pressure (SVP), and end diastolic pressures (EDP) most correlated with 1- and 10-year outcomes. Transplanted patients with SVP < 14 and non- transplanted patients with PCWP < 15 had 100% survival 1-year post-transplantation. CONCLUSION: For the first time, our study identifies that hemodynamic parameters most strongly correlate with 1- and 10-year outcomes in ACHD patients considered for transplantation, using a data-driven machine learning model.

From Other Journals: A Review of Recent Articles by Our Editorial Team.

In this review, we provide a brief description of recently published articles addressing topics relevant to pediatric cardiologists. This review includes (1) Fetal diagnosis, associated anomalies, and factors affecting outcomes in fetal congenitally corrected transposition of the great arteries (ccTGA), (2) The impact of Fontan-associated liver disease on heart and heart/liver transplant, (3) 1-year outcomes of the Harmony transcatheter pulmonary valve, (4) Risk factors associated with major adverse cardiac events in patients with pulmonary atresia and intact ventricular septum undergoing intervention, and (5) Benefits of pulmonary valve replacement in tetralogy of Fallot patients.

Associations Between Characteristics of Individuals With Fontan Circulation With Blood and Urine Biomarkers of Kidney Injury and Dysfunction.

Background Fontan circulation is associated with kidney injury and dysfunction, often unappreciated until Fontan circulatory failure. We hypothesized that cystatin C-estimated glomerular filtration rate (eGFR) would identify chronic kidney disease more frequently and that urine kidney injury biomarkers would be higher with declining Fontan physiological features. Methods and Results We enrolled 100 ambulatory individuals. Blood and urinary laboratory measurements were compared with demographics and clinically obtained data. Different eGFR equations were used for individuals aged ≥19 years and <19 years. Chronic kidney disease was defined as eGFR <90 mL/min per 1.73 m2. Median (25th-75th percentile) age was 19 (14-26) years, and 43% were female patients. Cystatin C eGFR detected chronic kidney disease (37%) in more patients than creatinine eGFR (11%). Cystatin C eGFR was positively associated, and skeletal muscle mass was negatively associated, with creatinine eGFR in both univariate (cystatin C eGFR ß=0.44±0.12, P=0.0006; skeletal muscle mass ß=-0.72±0.32, P=0.03) and multivariable analysis (cystatin C eGFR ß=0.43±0.12, P=0.0005; skeletal muscle mass ß=-0.69±0.29, P=0.02). Urine neutrophil gelatinase-associated lipocalin concentration correlated with Fontan pressure (r=0.28; P=0.04), ventricular end-diastolic pressure (r=0.28; P=0.04), and body fat mass (r=0.26; P=0.03). Conclusions Cystatin C eGFR identified more kidney dysfunction, likely attributable to creatinine eGFR being confounded by skeletal muscle mass. Elevated urine neutrophil gelatinase-associated lipocalin was associated with worse Fontan hemodynamics and higher percentage body fat, suggesting that higher venous pressure and higher adiposity are associated with ongoing kidney injury.

Pulmonary Complications in Patients With Fontan Circulation: JACC Review Topic of the Week.

The Fontan operation has resulted in significant improvement in survival of patients with single ventricle physiology. As a result, there is a growing population of individuals with Fontan physiology reaching adolescence and adulthood. Despite the improved survival, there are long-term morbidities associated with the Fontan operation. Pulmonary complications are common and may contribute to both circulatory and pulmonary insufficiency, leading ultimately to Fontan failure. These complications include restrictive lung disease, sleep abnormalities, plastic bronchitis, and cyanosis. Cyanosis post-Fontan procedure can be attributed to multiple causes including systemic to pulmonary venous collateral channels and pulmonary arteriovenous malformations. This review presents the unique cardiopulmonary interactions in the Fontan circulation. Understanding the cardiopulmonary interactions along with improved recognition and treatment of pulmonary abnormalities may improve the long-term outcomes in this growing patient population. Interventions focused on improving pulmonary function including inspiratory muscle training and endurance training have shown a promising effect post-Fontan procedure.

Surrogates of Muscle Mass on Cardiac MRI Correlate with Exercise Capacity in Patients with Fontan Circulation.

BACKGROUND: Sarcopenia is an increasingly recognized marker of frailty in cardiac patients. Patients with a history of congenital heart disease and Fontan procedure have a higher risk of developing progressive muscle wasting. Our objective was to determine if we could use routine cardiac MRI (CMR) for the surveillance of muscle wasting. METHODS: A retrospective study of all Fontan patients (n = 75) was conducted at our institution, with CMR performed from 2010 to 2022 and exercise stress testing performed within 12 months (4.3 ± 4.2 months). The skeletal muscle area (SMA) for the posterior paraspinal and anterior thoracic muscles were traced and indexed for body surface area (BSA). Patients were stratified by percentile into the upper and lower quartiles, and the two groups were compared. Multivariable regression was performed to control for sex and age. RESULTS: There was a significant positive association of both anterior (r = 0.34, p = 0.039) and paraspinal (r = 0.43, p = 0.007) SMA to peak VO2. Similarly, paraspinal but not anterior SMA was negatively associated with the VE/VCO2 (r = -0.45, p = 0.006). The upper quartile group had significantly more males (18/19 vs. 8/20; p = 0.0003) and demonstrated a significantly higher peak VO2 (32.2 ± 8.5 vs. 23.8 ± 4.7, p = 0.009), a higher peak RER (1.2 ± 0.1 vs. 1.1 ± 0.04, p = 0.007), and a significantly lower VE/VCO2 (32.9 ± 3.6 vs. 40.2 ± 6.2, p = 0.006) compared to the lowest quartile. The association of SMA to VO2 peak and VE/VCO2 was redemonstrated after controlling for sex and age. CONCLUSION: Thoracic skeletal muscle area may be an effective surrogate of muscle mass and is correlated to several measures of cardiorespiratory fitness post-Fontan. CMR would be an effective tool for the surveillance of sarcopenia in post-Fontan patients given its accessibility and routine use in these patients.

Isosorbide DiNitrate Effect on Hemodynamic Profile, Liver Stiffness, and Exercise Tolerance in Fontan Circulation (The NEET Clinical Trial).

After Fontan operation, decreased venous capacitance and venoconstriction are adaptive mechanisms to maintain venous return and cardiac output. The consequent higher venous pressure may adversely impact end-organ function, exercise capacity and result in worse clinical outcomes. This pilot study evaluated the safety and effect of isosorbide dinitrate (ISDN), a venodilator, on exercise capacity, peripheral venous pressure (PVP), and liver stiffness in patients with Fontan circulation. In this prospective single-arm trial, 15 individuals with Fontan circulation were evaluated at baseline and after 4 weeks of therapeutic treatment with ISDN. Primary aims were to assess the safety of ISDN and the effect on maximal exercise. We also aimed to evaluate the effect of ISDN on ultrasound-assessed liver stiffness, markers of submaximal exercise, and PVP at rest and peak exercise. Repeated measures t-tests were used to assess change in variables of interest in response to ISDN. Mean age was 23.5 ± 9.2 years (range 11.2-39.0 years), and 10/15 (67%) were male. There was no statistically significant change in peak VO2 (1401 ± 428 to 1428 ± 436 mL/min, p = 0.128), but VO2 at the anaerobic threshold increased (1087 ± 313 to 1115 ± 302 mL/min, p = 0.03). ISDN was also associated with a lower peak exercise PVP (22.5 ± 4.5 to 20.6 ± 3.0 mmHg, p = 0.015). Liver stiffness was lower with ISDN, though the difference was not statistically significant (2.3 ± 0.4 to 2.1 ± 0.5 m/s, p = 0.079). Of the patients completing the trial, mild headache was common (67%), but there were no major adverse events. Treatment with ISDN for 4 weeks is well-tolerated in patients with a Fontan circulation. ISDN is associated with an increase in VO2 at anaerobic threshold, lower peak PVP, and a trend toward lower liver stiffness. Larger, longer duration studies will be necessary to define the impact of ISDN on clinical outcomes in the Fontan circulation.Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT04297241.