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Outcomes of infants and children undergoing surgical repair of ventricular septal defect: a review of the literature and implications for research with an emphasis on pulmonary artery hypertension

Published online by Cambridge University Press:  20 May 2020

Anna G. Palladino-Davis
Affiliation:
Department of Preventive Medicine, Northwestern University, Chicago, IL, USA
Christopher S. Davis*
Affiliation:
Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
*
Author for correspondence: Christopher S. Davis, MD, MPH, FACS, Department of Surgery, Medical College of Wisconsin, 8701 W. Watertown Plank Road, Milwaukee, WI53226, USA. Tel: +1 414 955 1731; Fax: +1 414 955 0072; E-mail: [email protected]

Abstract

Background:

Pulmonary vascular disease resulting from CHDs may be the most preventable cause of pulmonary artery hypertension worldwide. Many children in developing countries still do not have access to early closure of clinically significant defects, and the long-term outcomes after corrective surgery remain unclear. Focused on long-term results after isolated ventricular septal defect repair, our review sought to determine the most effective medical therapy for the pre-operative management of elevated left-to-right shunts in patients with an isolated ventricular septal defect.

Methods:

We identified articles specific to the surgical repair of isolated ventricular septal defects. Specific parameters included the pathophysiology and pre-operative medical management of pulmonary over-circulation and outcomes.

Results:

Studies most commonly focused on histologic changes to the pulmonary vasculature and levels of thromboxanes, prostaglandins, nitric oxide, endothelin, and matrix metalloproteinases. Only 2/44 studies mentioned targeted pharmacologic management to any of these systems related to ventricular septal defect repair; no study offered evidence-based guidelines to manage pulmonary over-circulation with ventricular septal defects. Most studies with long-term data indicated a measurable frequency of pulmonary artery hypertension or diminished exercise capacity late after ventricular septal defect repair.

Conclusion:

Long-term pulmonary vascular and respiratory changes can occur in children after ventricular septal defect repair. Research should be directed at providing an evidenced-based approach to the medical management of infants and children with ventricular septal defects (and naturally all CHDs) to minimise consequences of pulmonary artery hypertension, particularly as defect repair may occur late in underprivileged societies.

Type
Review Article
Copyright
© The Author(s), 2020. Published by Cambridge University Press

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References

Mitchell, SC, Korones, SB, Berendes, HW. Congenital heart disease in 56,109 births. Incidence and natural history. Circulation 1971; 43: 323332.10.1161/01.CIR.43.3.323CrossRefGoogle ScholarPubMed
Roger, H.Recherches cliniques sur la communication congenitale de deux coeurs: pars inocclusion de septum interventriculaire. Bull Acad Natl Med 1879; 8: 10741094.Google Scholar
Mavroudis, C, Backer, CL, Jacobs, JP. Ventricular septal defect. In: Mavroudis, C, Backer, CL (eds). Pediatric Cardiac Surgery, 3rd edn. Mosby, Philadelphia, 2003: 298320.Google Scholar
Adatia, I, Kothari, SS, Feinstein, JA.Pulmonary hypertension associated with congenital heart disease: pulmonary vascular disease: the global perspective. Chest 2010; 137 (6 Suppl): 52S61S.10.1378/chest.09-2861CrossRefGoogle ScholarPubMed
Heath, D, Helmholz, HF Jr, Burchell, HB, Duschane, JW, Kirklin, JW, Edwards, JE.Relation between structural change in the small pulmonary arteries and the immediate reversibility of pulmonary hypertension following closure of ventricular and atrial septal defects. Circulation 1958; 18: 11671174.10.1161/01.CIR.18.6.1167CrossRefGoogle ScholarPubMed
Wagenvoort, CA, Neufeld, HN, Dushane, JW, Edwards, JE.The pulmonary arterial tree in ventricular septal defect. A quantitative study of anatomic features in fetuses, infants. and children. Circulation 1961; 23: 740748.10.1161/01.CIR.23.5.740CrossRefGoogle ScholarPubMed
Rabinovitch, M, Haworth, SG, Castaneda, AR, Nadas, AS, Reid, LM.Lung biopsy in congenital heart disease: a morphometric approach to pulmonary vascular disease. Circulation 1978; 58: 11071122.10.1161/01.CIR.58.6.1107CrossRefGoogle ScholarPubMed
Rabinovitch, M, Keane, JF, Norwood, WI, Castaneda, AR, Reid, L.Vascular structure in lung tissue obtained at biopsy correlated with pulmonary hemodynamic findings after repair of congenital heart defects. Circulation 1984; 69: 655667.10.1161/01.CIR.69.4.655CrossRefGoogle ScholarPubMed
Yeager, SB, Freed, MD, Keane, JF, Norwood, WI, Castaneda, AR.Primary surgical closure of ventricular septal defect in the first year of life: results in 128 infants. J Am Coll Cardiol 1984; 3: 12691276.10.1016/S0735-1097(84)80187-4CrossRefGoogle ScholarPubMed
Fleming, WH, Sarafian, LB, Leuschen, MP, et al. Serum concentrations of prostacyclin and thromboxane in children before, during, and after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1986; 92: 7378.10.1016/S0022-5223(19)35933-1CrossRefGoogle ScholarPubMed
Fried, R, Falkovsky, G, Newburger, J, et al.Pulmonary arterial changes in patients with ventricular septal defects and severe pulmonary hypertension. Pediatr Cardiol 1986; 7: 147154.10.1007/BF02424988CrossRefGoogle ScholarPubMed
Haworth, SG.Pulmonary vascular disease in ventricular septal defect: structural and functional correlations in lung biopsies from 85 patients, with outcome of intracardiac repair. J Pathol 1987; 152: 157168.10.1002/path.1711520304CrossRefGoogle ScholarPubMed
Adatia, I, Barrow, SE, Stratton, PD, Miall-Allen, VM, Ritter, JM, Haworth, SG.Thromboxane A2 and prostacyclin biosynthesis in children and adolescents with pulmonary vascular disease. Circulation 1993; 88: 21172122.10.1161/01.CIR.88.5.2117CrossRefGoogle ScholarPubMed
Adatia, I, Barrow, SE, Stratton, PD, Ritter, JM, Haworth, SG.Effect of intracardiac repair on biosynthesis of thromboxane A2 and prostacyclin in children with a left to right shunt. Br Heart J 1994; 72: 452456.10.1136/hrt.72.5.452CrossRefGoogle ScholarPubMed
Takaya, J, Teraguchi, M, Nogi, S, Ikemoto, Y, Kobayashi, Y.Relation between plasma nitrate and mean pulmonary arterial pressure in ventricular septal defect. Arch Dis Child 1998; 79: 498501.10.1136/adc.79.6.498CrossRefGoogle ScholarPubMed
Maeda, K, Yamaki, S, Nishiyama, M, Murakami, Y, Takahashi, Y, Takamoto, S.Pathological lesions causing pulmonary hypertension after closure of a ventricular septal defect. Jpn J Thorac Cardiovasc Surg 2003; 51: 430433.10.1007/BF02719596CrossRefGoogle ScholarPubMed
Pan, X, Zheng, Z, Hu, S, et al.Mechanisms of pulmonary hypertension related to ventricular septal defect in congenital heart disease. Ann Thorac Surg 2011; 92: 22152220.10.1016/j.athoracsur.2011.07.051CrossRefGoogle ScholarPubMed
Aydemir, NA, Harmandar, B, Karaci, AR, et al.Results for surgical closure of isolated ventricular septal defects in patients under one year of age. J Card Surg 2013; 28: 174179.10.1111/jocs.12073CrossRefGoogle ScholarPubMed
Bhasin, S, Gogia, P, Nair, R, TK, Sahoo. Perioperative sildenafil therapy for children with ventricular septal defects and associated pulmonary hypertension undergoing corrective surgery: a randomized control trial. Indian J Anaesth 2017; 61: 798802.10.4103/ija.IJA_210_17CrossRefGoogle Scholar
Sharma, VK, Joshi, S, Joshi, A, Kumar, G, Arora, H, Gard, A.Does intravenous sildenafil clinically ameliorate pulmonary hypertension during perioperative management of congenital heart diseases in children? – a prospective randomized study. Ann Card Anaesth 2015; 15: 510516.10.4103/0971-9784.166457CrossRefGoogle Scholar
Palma, G, Giordano, R, Russolillo, V, et al.Sildenafil therapy for pulmonary hypertension before and after pediatric congenital heart surgery. Tex Heart Inst J 2011; 38: 238242.Google ScholarPubMed
Bigdelian, H, Sedighi, M.The ole of preoperative sildenafil therapy in controlling of postoperative pulmonary hypertension in children with ventricular septal defects. J Cardiovasc Thorac Res 2017; 9: 179182.10.15171/jcvtr.2017.31CrossRefGoogle Scholar
El Midany, AA, Mostafa, EA, Azab, S, Hassan, GA.Perioperative sildenafil therapy for pulmonary hypertension in infants undergoing congenital cardiac defect closure. Interact Cardiovasc Thorac Surg 2013; 17: 963968.10.1093/icvts/ivt353CrossRefGoogle ScholarPubMed
Zeng, WJ, Lu, XL, Xiong, CM, et al.The efficacy and safety of sildenafil in patients with pulmonary artery hypertension associated with the different types of congenital heart disease. Clin Cardiol 2011; 34: 513518.10.1002/clc.20917CrossRefGoogle ScholarPubMed
Kirklin, JW, Dushane, JW.Repair of ventricular septal defect in infancy. Pediatrics 1961; 27: 961966.Google ScholarPubMed
Sigmann, JM, Stern, AM, Sloan, HE.Early surgical correction of large ventricular septal defects. Pediatrics 1967; 39: 413.Google ScholarPubMed
Wada, J, Iwa, T.Two-stage treatment of ventricular septal defect with pulmonary hypertension. Ann Thorac Surg 1969; 8: 415424.10.1016/S0003-4975(10)66072-9CrossRefGoogle ScholarPubMed
Hallidie-Smith, KA, Hollman, A, Cleland, WP, Bentall, HH, Goodwin, JF.Effects of surgical closure of ventricular septal defects upon pulmonary vascular disease. Br Heart J 1969; 31: 246260.10.1136/hrt.31.2.246CrossRefGoogle ScholarPubMed
Park, CD, Nicodemus, H, Downes, JJ, Miller, WW, Waldhausen, JA.Changes in pulmonary vascular resistance following closure of ventricular septal defects. Circulation 1969; 39 (5 Suppl 1): I193I200.10.1161/01.CIR.39.5S1.I-193CrossRefGoogle ScholarPubMed
Gotsman, MS, Beck, W, Barnard, CN, Schrire, V.Haemodynamic studies after repair of ventricular septal defect. Br Heart J 1969; 31: 6371.10.1136/hrt.31.1.63CrossRefGoogle ScholarPubMed
Lueker, RD, Vogel, JH, Blount, SG Jr. Cardiovascular abnormalities following surgery for left-to-right shunts. Observations in atrial septal defects, ventricular septal defects, and patent ductus arteriosus. Circulation 1969; 40: 785801.10.1161/01.CIR.40.6.785CrossRefGoogle ScholarPubMed
Maron, BJ, Redwood, DR, Hirshfeld, JW Jr, Goldstein, RE, Morrow, AG, Epstein, SE.Postoperative assessment of patients with ventricular septal defect and pulmonary hypertension. Response to intense upright exercise. Circulation 1973; 48: 864874.10.1161/01.CIR.48.4.864CrossRefGoogle ScholarPubMed
Friedli, B, Kidd, BS, Mustard, WT, Keith, JD.Ventricular septal defect with increased pulmonary vascular resistance. Late results of surgical closure. Am J Cardiol 1974; 33: 403409.10.1016/0002-9149(74)90323-3CrossRefGoogle ScholarPubMed
Weidman, WH, Blount, G, DuShane, J, Gersony, WM, Hayes, CJ, Nada, AS.Clinical course in ventricular septal defect. Circulation 1977; 56: I-56–I-69.Google ScholarPubMed
Sigmann, JM, Perry, BL, Gehrendt, DM, Stern, AM, Kirsh, MM, Sloan, HE.Ventricular septal defect: results after repair in infancy. Am J Cardiol 1977; 39: 6671.10.1016/S0002-9149(77)80013-1CrossRefGoogle ScholarPubMed
Hallidie-Smith, KA, Wilson, RS, Hart, A, Zeidifard, E.Functional status of patients with large ventricular septal defect and pulmonary vascular disease 6 to 16 years after surgical closure of their defect in childhood. Br Heart J 1977; 39: 10931101.10.1136/hrt.39.10.1093CrossRefGoogle ScholarPubMed
McNicholas, KW, Bowman, FO, Hayes, CJ, Edie, RN, Malm, JR.Surgical management of ventricular septal defects in infants. J Thorac Cardiovasc Surg 1978; 75: 346353.10.1016/S0022-5223(19)41260-9CrossRefGoogle ScholarPubMed
Richardson, JV, Schieken, RM, Lauer, RM, Stewart, P, Doty, DB.Repair of large ventricular septal defects in infants and small children. Ann Surg 1982; 195: 318322.10.1097/00000658-198203000-00012CrossRefGoogle ScholarPubMed
McNamara, DG, Latson, LA.Long-term follow-up of patients with malformations for which definitive surgical repair has been available for 25 years or more. Am J Cardiol 1982; 50: 560568.10.1016/0002-9149(82)90325-3CrossRefGoogle ScholarPubMed
Blake, RS, Chung, EE, Wesley, H, Hallidie-Smith, KA.Conduction defects, ventricular arrhythmias, and late death after surgical closure of ventricular septal defect. Br Heart J 1982; 47: 305315.CrossRefGoogle ScholarPubMed
Haneda, K, Ishizawa, E, Yamaki, S, et al.Surgical closure of ventricular septal defect in the first year of life: forty-three consecutive successful cases. Tohoku J Exp Med 1988; 156: 3945.10.1620/tjem.156.39CrossRefGoogle ScholarPubMed
Moller, JH, Patton, C, Varco, RL, Lillehei, CW.Late results (30 to 35 years) after operative closure of isolated ventricular septal defect from 1954 to 1960. Am J Cardiol 1991; 68: 14911497.10.1016/0002-9149(91)90284-RCrossRefGoogle ScholarPubMed
Hardin, JT, Muskett, AD, Canter, CE, Martin, TC, Spray, TL.Primary surgical closure of large ventricular septal defects in small infants. Ann Thorac Surg 1992; 53: 397401.10.1016/0003-4975(92)90257-5CrossRefGoogle ScholarPubMed
Backer, CL, Winters, RC, Zales, VR, et al.Restrictive ventricular septal defect: how small is too small to close? Ann Thorac Surg 1993; 56: 10141018; discussion 1018–1019.10.1016/0003-4975(95)90006-3CrossRefGoogle Scholar
Meijboom, F, Szatmari, A, Utens, E, et al.Long-term follow-up after surgical closure of ventricular septal defect in infancy and childhood. J Am Coll Cardiol 1994; 24: 13581364.10.1016/0735-1097(94)90120-1CrossRefGoogle ScholarPubMed
Haneda, K, Sato, N, Togo, T, Miura, M, Hata, M, Mohri, H.Late results after correction of ventricular septal defect with severe pulmonary hypertension. Tohoku J Exp Med 1994; 174: 4148.10.1620/tjem.174.41CrossRefGoogle ScholarPubMed
Ikawa, S, Shimazaki, Y, Nakano, S, Kobayashi, J, Matsuda, H, Kawashima, Y.Pulmonary vascular resistance during exercise late after repair of large ventricular septal defects. Relation to age at the time of repair. J Thorac Cardiovasc Surg 1995; 109: 12181224.10.1016/S0022-5223(95)70206-7CrossRefGoogle ScholarPubMed
Reddy, VM, McElhinney, DB, Sagrado, T, Parry, AJ, Teitel, DF, Hanley, FL.Results of 102 cases of complete repair of congenital heart defects in patients weighing 700 to 2500 grams. J Thorac Cardiovasc Surg 1999; 117: 324331.10.1016/S0022-5223(99)70430-7CrossRefGoogle ScholarPubMed
Nieminen, HP, Jokinen, EV, Sairanen, HI.Late results of pediatric cardiac surgery in Finland: a population-based study with 96% follow-up. Circulation 2001; 104: 570575.10.1161/hc3101.093968CrossRefGoogle ScholarPubMed
Kannan, BR, Sivasankaran, S, Tharakan, JA, et al.Long-term outcome of patients operated for large ventricular septal defects with increased pulmonary vascular resistance. Indian Heart J 2003; 55: 161166.Google ScholarPubMed
Bol-Raap, G, Weerheim, J, Kappetein, AP, Witsenburg, M, Bogers, AJ.Follow-up after surgical closure of congenital ventricular septal defect. Eur J Cardiothorac Surg 2003; 24: 511515.10.1016/S1010-7940(03)00430-5CrossRefGoogle ScholarPubMed
Roos-Hesselink, JW, Meijboom, FJ, Spitaels, SE, et al.Outcome of patients after surgical closure of ventricular septal defect at young age: longitudinal follow-up of 22–34 years. Eur Heart J 2004; 25: 10571062.10.1016/j.ehj.2004.04.012CrossRefGoogle ScholarPubMed
Scully, BB, Morales, DL, Zafar, F, McKenzie, ED, Fraser, CD Jr, Heinle, JS.Current expectations for surgical repair of isolated ventricular septal defects. Ann Thorac Surg 2010; 89: 544549; discussion 550–551.10.1016/j.athoracsur.2009.10.057CrossRefGoogle ScholarPubMed
Anderson, BR, Stevens, KN, Nicolson, SC, et al.Contemporary outcomes of surgical ventricular septal defect closure. J Thorac Cardiovasc Surg 2013; 145: 641647.10.1016/j.jtcvs.2012.11.032CrossRefGoogle ScholarPubMed
Yang, J, Yang, L, Yu, S, et al.Transcatheter versus surgical closure of perimembranous ventricular septal defects in children: a randomized controlled trial. J Am Coll Cardiol 2014; 63: 11591168.CrossRefGoogle ScholarPubMed
Heiberg, J, Petersen, AK, Laustsen, S, Hjortdal, VE.Abnormal ventilatory response to exercise in young adults operated for ventricular septal defect in early childhood: a long-term follow-up. Int J Cardiol 2015; 194: 26.10.1016/j.ijcard.2015.05.071CrossRefGoogle ScholarPubMed
Gabriels, C, Van De Bruaene, A, Helsen, F, et al.Recall of patients discharged from follow-up after repair of isolated congenital shunt lesions. Int J Cardiol 2016; 221: 314320.10.1016/j.ijcard.2016.07.066CrossRefGoogle ScholarPubMed
Gabriels, C, De Backer, J, Pasquet, A, et al.Long-term outcome of patients with perimembranous ventricular septal defect: results from the Belgian registry on adult congenital heart disease. Cardiology 2017; 136: 147155.CrossRefGoogle ScholarPubMed
Nederend, I, de Geus, EJC, Blom, NA, Ten Harkel, ADJ.Long-term follow-up after ventricular septal defect repair in children: cardiac autonomic control, cardiac function and exercise capacity. Eur J Cardiothorac Surg 2018; 53: 10821088.10.1093/ejcts/ezx438CrossRefGoogle ScholarPubMed
Gabriels, C, Buys, R, Van de Bruaene, A, et al.Serial pulmonary vascular resistance assessment in patients late after ventricular septal defect repair. Int J Cardiol 2019; 282: 3843.10.1016/j.ijcard.2018.12.044CrossRefGoogle ScholarPubMed
Rex, CE, Eckerstrom, F, Heiberg, J, et al.Surgical closure of a ventricular septal defect in early childhood leads to altered pulmonary function in adulthood: A long-term follow-up. Int J Cardiol 2019; 274: 100105.10.1016/j.ijcard.2018.06.109CrossRefGoogle ScholarPubMed
Heath, D, Edwards, JE.The pathology of hypertensive pulmonary vascular disease. Circulation 1958; 18: 533547.CrossRefGoogle ScholarPubMed
Stewart, DJ, Levy, RD, Cernacek, P, Langleben, D.Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991; 114: 464469.10.7326/0003-4819-114-6-464CrossRefGoogle ScholarPubMed
Komai, H, Adatia, IT, Elliott, MJ, de Leval, MR, Haworth, SG.Increased plasma levels of endothelin-1 after cardiopulmonary bypass in patients with pulmonary hypertension and congenital heart disease. J Thorac Cardiovasc Surg 1993; 106: 473478.10.1016/S0022-5223(19)34082-6CrossRefGoogle ScholarPubMed
Yoshibayashi, M, Nishioka, K, Nakao, K, et al.Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects. Evidence for increased production of endothelin in pulmonary circulation. Circulation 1991; 84: 22802285.10.1161/01.CIR.84.6.2280CrossRefGoogle ScholarPubMed
Botney, MD.Role of hemodynamics in pulmonary vascular remodeling: implications for primary pulmonary hypertension. Am J Respir Crit Care Med 1999; 159: 361364.CrossRefGoogle ScholarPubMed
Rabinovitch, M, Konstam, MA, Gamble, WJ, et al.Changes in pulmonary blood flow affect vascular response to chronic hypoxia in rats. Circ Res 1983; 52: 432441.10.1161/01.RES.52.4.432CrossRefGoogle ScholarPubMed
O’Blenes, SB, Fischer, S, McIntyre, B, Keshavjee, S, Rabinovitch, M.Hemodynamic unloading lead to regression of pulmonary vascular disease in rats. J Thorac Cardiovasc Surg 2001; 121: 279289.10.1067/mtc.2001.111657CrossRefGoogle ScholarPubMed
Mata-Greenwood, E, Meyrick, B, Steinhorn, RH, Fineman, JR, Black, SM.Alterations in TGF-beta1 expression in lambs with increased blood flow and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2003; 285: L209L221.CrossRefGoogle ScholarPubMed
Wedgwood, S, Devol, JM, Grobe, A, et al.Fibroblast growth factor-2 expression is altered in lambs with increased pulmonary blood flow and pulmonary hypertension. Pediatr Res 2007; 61: 3236.CrossRefGoogle ScholarPubMed
Lévy, M, Maurey, C, Celermajer, DS, et al.Impaired apoptosis of pulmonary endothelial cells is associated with intimal proliferation and irreversibility of pulmonary hypertension in congenital heart disease. J Am Coll Cardiol 2007; 49: 803810.10.1016/j.jacc.2006.09.049CrossRefGoogle ScholarPubMed
Smadja, DM, Gaussem, P, Mauge, L, et al.Circulating endothelial cells: a new candidate biomarker of irreversible pulmonary hypertension secondary to congenital heart disease. Circulation 2009; 119: 374381.10.1161/CIRCULATIONAHA.108.808246CrossRefGoogle ScholarPubMed
Smadja, DM, Gaussem, P, Mauge, L, et al.Comparison of endothelial biomarkers according to reversibility of pulmonary hypertension secondary to congenital heart disease. Pediatr Cardiol 2010; 31: 657662.10.1007/s00246-010-9674-0CrossRefGoogle ScholarPubMed
Diller, GP, van Eijl, S, Okonko, DO, et al.Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation 2008; 117: 30203030.10.1161/CIRCULATIONAHA.108.769646CrossRefGoogle ScholarPubMed
Galie, N, Manes, A, Palazzini, M, et al.Management of pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s syndrome. Drugs 2008; 68: 10491066.10.2165/00003495-200868080-00004CrossRefGoogle ScholarPubMed
Lillehei, CW, Cohen, M, Warden, HE, Ziegler, NR, Varco, RL.The results of direct vision closure of ventricular septal defects in eight patients by means of controlled cross circulation. Surg Gynecol Obstet 1955; 101: 446466.Google ScholarPubMed
Saxena, A.Status of pediatric cardiac care in developing countries. Children (Basel) 2019; 6: 34.Google ScholarPubMed
Rashid, U, Qureshi, A, Hyder, S, et al.Pattern of congenital heart disease in a developing country tertiary care center: factors associated with delayed diagnosis. Ann Pediatr Cardiol 2016; 9: 210.10.4103/0974-2069.189125CrossRefGoogle Scholar
Yacoub, MH.Establishing paediatric cardiovascular services in the developing world: a wake-up call. Circulation 2007; 116: 18761878.CrossRefGoogle ScholarPubMed