Abstract
The objective of this study was describe the impact of sildenafil on echocardiographic measures of myocardial performance in children and young adults with a functional single-ventricle physiology late after Fontan surgery. A double-blind, placebo-controlled, crossover trial was conducted in children and young adults after the Fontan operation at a single pediatric center. Subjects were randomized to receive placebo or sildenafil (20 mg tid) for 6 weeks. After a 6-week washout period, subjects were crossed for an additional 6 weeks. Each subject underwent an echocardiogram at the start and finish of each phase. A total of 27 subjects completed study testing at a mean age of 14.9 years and a mean time from Fontan surgery of 11.3 years. After sildenafil, subjects demonstrated improvement in their myocardial performance index (MPI; −0.051; 95% CI −0.095, −0.0077; p 0.02) and in the product of the velocity time integral (VTI) of the dominant outflow tract and the heart rate (HR; 110 cm × bpm; 95% CI 7.5, 220; p = 0.04). Measures of diastolic performance, including inflow velocities, myocardial velocities, and the ratio of blood pool velocity to myocardial velocity during passive inflow, did not change. In this cohort, there were significant improvements in both the MPI and the product of the VTI × HR after 6 weeks of treatment with sildenafil. These findings suggest that sildenafil may be a useful therapy to improve or maintain ventricular performance in select patients after the Fontan operation.
Similar content being viewed by others
References
Anderson PA, Sleeper LA, Mahony L, Colan SD, Atz AM, Breitbart RE et al (2008) Contemporary outcomes after the Fontan procedure: a Pediatric Heart Network multicenter study. J Am Coll Cardiol 52:85–98
Behling A, Rohde LE, Colombo FC, Goldraich LA, Stein R, Clausell N (2008) Effects of 5′-phosphodiesterase four-week long inhibition with sildenafil in patients with chronic heart failure: a double-blind, placebo-controlled clinical trial. J Card Fail 14:189–197
Caldas MC, Meira ZA, Barbosa MM (2008) Evaluation of 107 patients with sickle cell anemia through tissue Doppler and myocardial performance index. J Am Soc Echocardiogr 21:1163–1167
Canter CE, Shaddy RE, Bernstein D, Hsu DT, Chrisant MR, Kirklin JK et al (2007) Indications for heart transplantation in pediatric heart disease: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young; the Councils on Clinical Cardiology, Cardiovascular Nursing, and Cardiovascular Surgery and Anesthesia; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 115:658–676
Cheung EW, Lam WW, Cheung SC, Cheung YF (2008) Functional implications of the right ventricular myocardial performance index in patients after surgical repair of tetralogy of Fallot. Heart Vessels 23:112–117
Diller GP, Giardini A, Dimopoulos K, Gargiulo G, Muller J, Derrick G et al (2010) Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients. Eur Heart J 31(24):3073–3083
Fontan F, Baudet E (1971) Surgical repair of tricuspid atresia. Thorax 26:240–248
Goldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD et al (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
Guazzi M, Vicenzi M, Arena R, Guazzi MD (2011) PDE5-inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry and clinical status in patients with stable systolic heart failure: results of a 1-year prospective, randomized, placebo-controlled study. Circ Heart Fail 4(1):8–17
Jenkins PC, Chinnock RE, Jenkins KJ, Mahle WT, Mulla N, Sharkey AM et al (2008) Decreased exercise performance with age in children with hypoplastic left heart syndrome. J Pediatr 152:507–512
Kenward MG, Roger JH (2010) The use of baseline covariates in crossover studies. Biostatistics 11:1–17
Klimes K, Ovroutski S, Abdul-Khaliq H, Ewert P, Alexi-Meskishvili V, Kuehne T et al (2009) Exercise capacity reflects ventricular function in patients having the Fontan circulation. Cardiol Young 19(4):340–345
Kreutzer G, Galindez E, Bono H, De Palma C, Laura JP (1973) An operation for the correction of tricuspid atresia. J Thorac Cardiovasc Surg 66:613–621
Lai WW, Geva T, Shirali GS, Frommelt PC, Humes RA, Brook MM et al (2006) Guidelines and standards for performance of a pediatric echocardiogram: a report from the Task Force of the Pediatric Council of the American Society of Echocardiography. J Am Soc Echocardiogr 19:1413–1430
Morner S, Lindqvist P, Waldenstrom A, Kazzam E (2008) Right ventricular dysfunction in hypertrophic cardiomyopathy as evidenced by the myocardial performance index. Int J Cardiol 124:57–63
Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL et al (2009) Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J Am Coll Cardiol 53:207–215
Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A et al (2007) Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 116:238–248
Patel N, Mills JF, Cheung MM (2009) Use of the myocardial performance index to assess right ventricular function in infants with pulmonary hypertension. Pediatr Cardiol 30:133–137
Pokreisz P, Vandenwijngaert S, Bito V, Van den Bergh A, Lenaerts I, Busch C et al (2009) Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice. Circulation 119:408–416
Rychik J (2010) Forty years of the Fontan operation: a failed strategy. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 13:96–100
Sarkar H, Siddique MA, Haque KM, Ahmed CM, Mahmood M, Bhattacharjee B et al (2008) Evaluation of left ventricular global function using Doppler myocardial performance index in patients with systemic hypertension. Mymensingh Med J 17(Suppl):S65–S71
Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER et al (2005) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11:214–222
Tei C, Ling LH, Hodge DO, Bailey KR, Oh JK, Rodeheffer RJ et al (1995) New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function: a study in normals and dilated cardiomyopathy. J Cardiol 26:357–366
Tweddell JS, Nersesian M, Mussatto KA, Nugent M, Simpson P, Mitchell ME et al (2009) Fontan palliation in the modern era: factors impacting mortality and morbidity. Ann Thorac Surg 88:1291–1299
Zhang YQ, Sun K, Zhu SL, Wu LP, Chen GZ, Zhang ZF et al (2008) Doppler myocardial performance index in assessment of ventricular function in children with single ventricles. World J Pediatr 4:109–113
Zhang M, Takimoto E, Hsu S, Lee DI, Nagayama T, Danner T et al (2010) Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5. J Am Coll Cardiol 56:2021–2030
Acknowledgments
The authors thank Erin Davis, Anysia Fedec, the staff of the Echocardiography Laboratory, and the staff of the Investigational Pharmacy at The Children’s Hospital of Philadelphia for their assistance and contributions to this work. This study was supported by grants from the The Mark H. and Blanche M. Harrington Family Foundation and from Big Hearts to Little Hearts. D. J. G. received support from NIH T32 Grant no. HL07915.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Goldberg, D.J., French, B., Szwast, A.L. et al. Impact of Sildenafil on Echocardiographic Indices of Myocardial Performance After the Fontan Operation. Pediatr Cardiol 33, 689–696 (2012). https://doi.org/10.1007/s00246-012-0196-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00246-012-0196-9