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

Amee M Bigelow; Kyle W Riggs; David L S Morales; Alexander R Opotowsky; Adam M Lubert; Jonathan R Dillman; Gruschen R Veldtman; Haleh C Heydarian; Andrew T Trout; David S Cooper; Stuart L Goldstein; Clifford Chin; Joseph J Palermo; Nicholas J Ollberding; Wayne A Mays; Tarek Alsaied

doi:10.1007/s00246-023-03156-3

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

Pediatr Cardiol. 2023 Apr 21:1-9. doi: 10.1007/s00246-023-03156-3. Online ahead of print.

Authors

Amee M Bigelow^{1

2}, Kyle W Riggs^{3

4}, David L S Morales³, Alexander R Opotowsky⁵, Adam M Lubert³, Jonathan R Dillman⁶, Gruschen R Veldtman⁷, Haleh C Heydarian³, Andrew T Trout⁶, David S Cooper³, Stuart L Goldstein⁸, Clifford Chin³, Joseph J Palermo⁹, Nicholas J Ollberding¹⁰, Wayne A Mays³, Tarek Alsaied^{3

11}

Affiliations

¹ Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Drive, Cincinnati, OH, 45229, USA. amee.bigelow@nationwidechildrens.org.
² Department of Pediatrics, The Heart Center, Nationwide Children's Hospital, The Ohio State University, 700 Children's Drive, Columbus, OH, 43205, USA. amee.bigelow@nationwidechildrens.org.
³ Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Drive, Cincinnati, OH, 45229, USA.
⁴ Department of Cardiovascular and Thoracic Surgery, Northwell Health, Manhasset, NY, USA.
⁵ Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Drive, Cincinnati, OH, 45229, USA. Sasha.opotowsky@cchmc.org.
⁶ Department of Radiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁷ Scottish Adult Congenital Cardiac Service and University of Glasgow, Institute of Cardiovascular Medicine and Sciences, Golden Jubilee Hospital, Glasgow, UK.
⁸ Faculty of Medicine, Center for Acute Care Nephrology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
⁹ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
¹⁰ Division of Biostatistics and Epidemiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
¹¹ Pittsburgh Children's Hospital Medical Center, The Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, PA, USA.

Abstract

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.

Keywords: Congenital heart disease; Exercise capacitance; Fontan circulation; Isosorbide dinitrate; Liver stiffness; Venous capacitance.

Associated data

ClinicalTrials.gov/NCT04297241