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Effect of Sildenafil on Pressure–Volume Loop Measures of Ventricular Function in Fontan Patients

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Abstract

Sildenafil has been reported to improve exercise capacity in Fontan patients, but the physiologic mechanisms behind these findings are not completely understood. The objective of this study was to study the acute effect of sildenafil on pressure–volume loop (PVL) measures of ventricular function in Fontan patients. Patients after Fontan operation who were presenting for a clinically indicated catheterization were enrolled. Patients were randomized in a double-blinded fashion to receive placebo (n = 9) or sildenafil (n = 10) 30–90 min prior to catheterization. PVLs were recorded using microconductance catheters at baseline and after infusion of dobutamine (10 mcg/kg/min). The primary outcome was change in ventriculoarterial (VA) coupling. For the entire cohort, VA coupling trended toward improvement with dobutamine (1.4 ± 0.4 to 1.8 ± 0.9, p = 0.07). End-systolic elastance showed improvement (2.6 ± 0.9 to 3.8 ± 1.4 mmHg m2/ml, p < 0.01) with dobutamine infusion. The cohorts had similar VA coupling at baseline (p = 0.32), but the sildenafil cohort trended toward having less of an improvement in VA coupling with dobutamine stress (p = 0.06). There were no differences between PVL measures of systolic or diastolic function between treatment groups, both at baseline and after dobutamine infusion. Patients with Fontan circulation had improved contractility and trended toward improvement in VA coupling with dobutamine stress. Acute sildenafil administration was not associated with improved PVL measurements of ventricular function in this population. These results suggest that clinical improvements seen with administration of sildenafil in Fontan patients are not associated with an acute improvement in ventricular function.

Clinical Trial Registration: www.clinicaltrials.gov; Clinicaltrials.gov Identifier: NCT01815502.

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References

  1. Anderson PA, Sleeper LA, Mahony L, Colan SD, Atz AM, Breitbart RE, Gersony WM, Gallagher D, Geva T, Margossian R, McCrindle BW, Paridon S, Schwartz M, Stylianou M, Williams RV, Clark BJ 3rd (2008) Contemporary outcomes after the Fontan procedure: a Pediatric Heart Network multicenter study. J Am Coll Cardiol 52:85–98

    Article  PubMed Central  PubMed  Google Scholar 

  2. Bernstein D, Naftel D, Chin C, Addonizio LJ, Gamberg P, Blume ED, Hsu D, Canter CE, Kirklin JK, Morrow WR (2006) Outcome of listing for cardiac transplantation for failed Fontan: a multi-institutional study. Circulation 114:273–280

    Article  CAS  PubMed  Google Scholar 

  3. Binkley PF, Murray KD, Watson KM, Myerowitz PD, Leier CV (1991) Dobutamine increases cardiac output of the total artificial heart. Implications for vascular contribution of inotropic agents to augmented ventricular function. Circulation 84:1210–1215

    Article  CAS  PubMed  Google Scholar 

  4. Binotto MA, Maeda NY, Lopes AA (2008) Altered endothelial function following the Fontan procedure. Cardiol Young 18:70–74

    Article  PubMed  Google Scholar 

  5. Borgdorff MA, Bartelds B, Dickinson MG, Boersma B, Weij M, Zandvoort A, Sillje HH, Steendijk P, de Vroomen M, Berger RM (2012) Sildenafil enhances systolic adaptation, but does not prevent diastolic dysfunction, in the pressure-loaded right ventricle. Eur J Heart Fail 14:1067–1074

    Article  CAS  PubMed  Google Scholar 

  6. Bussotti M, Montorsi P, Amato M, Magini A, Baldassarre D, Tantardini F, Veglia F, Agostoni P (2008) Sildenafil improves the alveolar-capillary function in heart failure patients. Int J Cardiol 126:68–72

    Article  PubMed  Google Scholar 

  7. Ciliberti P, Giardini A (2011) Impact of oral chronic administration of sildenafil in children and young adults after the Fontan operation. Future Cardiol 7:609–612

    Article  CAS  PubMed  Google Scholar 

  8. Cucchini F, Bolognesi R, Javernaro A, Zeppellini R, De Domenico R, Visioli O (1994) Do inotropic drugs always induce a positive lusitropic effect? A comparison between k-strophanthidin and dobutamine in patients with coronary artery disease. Eur Heart J 15:1666–1672

    CAS  PubMed  Google Scholar 

  9. Dean PN, Hillman DG, McHugh KE, Gutgesell HP (2011) Inpatient costs and charges for surgical treatment of hypoplastic left heart syndrome. Pediatrics 128(5):e1181–e1186

    Article  PubMed  Google Scholar 

  10. Fraisse A, Butrous G, Taylor MB, Oakes M, Dilleen M, Wessel DL (2011) Intravenous sildenafil for postoperative pulmonary hypertension in children with congenital heart disease. Intensive Care Med 37:502–509

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Fredriksen PM, Therrien J, Veldtman G, Warsi MA, Liu P, Siu S, Williams W, Granton J, Webb G (2001) Lung function and aerobic capacity in adult patients following modified Fontan procedure. Heart 85:295–299

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Gajarski RJ, Towbin JA, Garson A Jr (1996) Fontan palliation versus heart transplantation: a comparison of charges. Am Heart J 131:1169–1174

    Article  CAS  PubMed  Google Scholar 

  13. Giardini A, Hager A, Pace Napoleone C, Picchio FM (2008) Natural history of exercise capacity after the Fontan operation: a longitudinal study. Ann Thorac Surg 85:818–821

    Article  PubMed  Google Scholar 

  14. Giardini A, Balducci A, Specchia S, Gargiulo G, Bonvicini M, Picchio FM (2008) Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J 29:1681–1687

    Article  CAS  PubMed  Google Scholar 

  15. Goldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD, Wernovsky G, Paridon SM, Rychik J (2011) Impact of oral sildenafil on exercise performance in children and young adults after the Fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation 123:1185–1193

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Haseyama K, Satomi G, Yasukochi S, Matsui H, Harada Y, Uchita S (2006) Pulmonary vasodilation therapy with sildenafil citrate in a patient with plastic bronchitis after the Fontan procedure for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg 132:1232–1233

    Article  PubMed  Google Scholar 

  17. Khairy P, Ionescu-Ittu R, Mackie AS, Abrahamowicz M, Pilote L, Marelli AJ (2010) Changing mortality in congenital heart disease. J Am Coll Cardiol 56:1149–1157

    Article  PubMed  Google Scholar 

  18. Loganathan S, Radovits T, Wirotanseng IR, Veres G, Hagl S, Szabo G (2007) Effects of vardenafil, a selective phosphodiesterase-5-inhibitor, on cardiovascular function in a rat model. BMC Pharmacol 7:1

    Article  Google Scholar 

  19. Loganathan S, Radovits T, Korkmaz S, Hirschberg K, Barnucz E, Weymann A, Bomicke T, Arif R, Karck M, Szabo G (2012) Enhancement of myocardial and vascular function after phosphodiesterase-5 inhibition in a rat model. Thorac Cardiovasc Surg 60:247–254

    PubMed  Google Scholar 

  20. Manlhiot C, Knezevich S, Radojewski E, Cullen-Dean G, Williams WG, McCrindle BW (2009) Functional health status of adolescents after the Fontan procedure—comparison with their siblings. Can J Cardiol 25:e294–e300

    Article  PubMed Central  PubMed  Google Scholar 

  21. McCrindle BW, Williams RV, Mitchell PD, Hsu DT, Paridon SM, Atz AM, Li JS, Newburger JW (2006) Relationship of patient and medical characteristics to health status in children and adolescents after the Fontan procedure. Circulation 113:1123–1129

    Article  PubMed  Google Scholar 

  22. Mitani Y, Ohashi H, Takabayashi S, Shimpo H, Komada Y (2011) Acute effect of sildenafil on hypoxemic patients (excluding those with Eisenmenger syndrome) with incurable congenital heart disease and disturbed pulmonary vasculature in the mid-term follow-up. Int J Cardiol 146:273–274

    Article  PubMed  Google Scholar 

  23. Morchi GS, Ivy DD, Duster MC, Claussen L, Chan KC, Kay J (2009) Sildenafil increases systemic saturation and reduces pulmonary artery pressure in patients with failing fontan physiology. Congenit Heart Dis 4:107–111

    Article  PubMed Central  PubMed  Google Scholar 

  24. Moss AJ, Allen HD (2008) Moss and Adams’ heart disease in infants, children, and adolescents: including the fetus and young adult, 7th edn. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  25. Ovroutski S, Ewert P, Miera O, Alexi-Meskishvili V, Peters B, Hetzer R, Berger F (2010) Long-term cardiopulmonary exercise capacity after modified Fontan operation. Eur J Cardiothorac Surg 37:204–209

    Article  PubMed  Google Scholar 

  26. Pingitore A, Aquaro GD, Lorenzoni V, Gallotta M, De Marchi D, Molinaro S, Cospite V, Passino C, Emdin M, Lombardi M, Lionetti V, L’Abbate A (2013) Influence of preload and afterload on stroke volume response to low-dose dobutamine stress in patients with non-ischemic heart failure: a cardiac MR study. Int J Cardiol 166:475–481

    Article  PubMed  Google Scholar 

  27. Rabelo ER, Ruschel K, Moreno H Jr, Rubira M, Consolim-Colombo FM, Irigoyen MC, Rohde LE (2008) Venous endothelial function in heart failure: comparison with healthy controls and effect of clinical compensation. Eur J Heart Fail 10(8):758–764

    Article  CAS  PubMed  Google Scholar 

  28. Reinhardt Z, Uzun O, Bhole V, Ofoe V, Wilson D, Onuzo O, Wright JG, Stumper O (2010) Sildenafil in the management of the failing Fontan circulation. Cardiol Young 20:522–525

    Article  PubMed  Google Scholar 

  29. Sarkola T, Jaeggi E, Slorach C, Hui W, Bradley T, Redington AN (2013) Assessment of vascular remodeling after the Fontan procedure using a novel very high resolution ultrasound method: arterial wall thinning and venous thickening in late follow-up. Heart Vessels 28:66–75

    Article  PubMed  Google Scholar 

  30. Schwedler G, Lindinger A, Lange PE, Sax U, Olchvary J, Peters B, Bauer U, Hense HW (2011) Frequency and spectrum of congenital heart defects among live births in Germany: a study of the competence network for congenital heart defects. Clin Res Cardiol 100:1111–1117

  31. Shabanian R, Shahbaznejad L, Razaghian A, Kiani A, Rahimzadeh M, Seifirad S, Kocharian A, Gilani JS, Navabi MA (2012) Sildenafil and ventriculo-arterial coupling in Fontan-palliated patients: a noninvasive echocardiographic assessment. Pediatr Cardiol 34:129–134

  32. Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, Ross RD, Pahl E, Blume ED, Dodd DA, Rosenthal DN, Burr J, LaSalle B, Holubkov R, Lukas MA, Tani LY (2007) Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA 298:1171–1179

    Article  PubMed  Google Scholar 

  33. Shishido T, Hayashi K, Shigemi K, Sato T, Sugimachi M, Sunagawa K (2000) Single-beat estimation of end-systolic elastance using bilinearly approximated time-varying elastance curve. Circulation 102:1983–1989

    Article  CAS  PubMed  Google Scholar 

  34. Sperandio PA, Oliveira MF, Rodrigues MK, Berton DC, Treptow E, Nery LE, Almeida DR, Neder JA (2012) Sildenafil improves microvascular O2 delivery-to-utilization matching and accelerates exercise O2 uptake kinetics in chronic heart failure. Am J Physiol Heart Circ Physiol 303:H1474–H1480

    Article  CAS  PubMed  Google Scholar 

  35. Uzark K, Lincoln A, Lamberti JJ, Mainwaring RD, Spicer RL, Moore JW (1998) Neurodevelopmental outcomes in children with Fontan repair of functional single ventricle. Pediatrics 101:630–633

    Article  CAS  PubMed  Google Scholar 

  36. Uzun O, Wong JK, Bhole V, Stumper O (2006) Resolution of protein-losing enteropathy and normalization of mesenteric Doppler flow with sildenafil after Fontan. Ann Thorac Surg 82:e39–e40

    Article  PubMed  Google Scholar 

  37. Walker DK, Ackland MJ, James GC, Muirhead GJ, Rance DJ, Wastall P, Wright PA (1999) Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica 29:297–310

    Article  CAS  PubMed  Google Scholar 

  38. Zelis R, Flaim SF (1982) Alterations in vasomotor tone in congestive heart failure. Prog Cardiovasc Dis 24:437–459

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to acknowledge Dr. Paul Nietert for his contribution to the statistical analysis.

Funding Sources

This work was supported by the American Heart Association Mentored Clinical Research Program Grant 13CRP14780092 (author: R.B. & A.A.). This work was supported in part by the National Center for Advancing Translational Sciences (UL1TR000062). This work was supported by NIH/NHLBI Grant 5T32-HL07710-19 (author: S.C.)

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  1. Division of Cardiology, Department of Pediatrics, Medical University of South Carolina, 165 Ashley Avenue, MSC 915, Charleston, SC, 29425, USA

    Ryan J. Butts, Shahryar M. Chowdhury, George H. Baker, Varsha Bandisode, Andrew J. Savage & Andrew M. Atz

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  2. Shahryar M. Chowdhury
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Correspondence to Ryan J. Butts.

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Butts, R.J., Chowdhury, S.M., Baker, G.H. et al. Effect of Sildenafil on Pressure–Volume Loop Measures of Ventricular Function in Fontan Patients. Pediatr Cardiol 37, 184–191 (2016). https://doi.org/10.1007/s00246-015-1262-x

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  • DOI: https://doi.org/10.1007/s00246-015-1262-x

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