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BMC Pediatrics
Published in: BMC Pediatrics 1/2019

Open Access 01-12-2019 | Minoxidil | Research article

Minoxidil versus placebo in the treatment of arterial wall hypertrophy in children with Williams Beuren Syndrome: a randomized controlled trial

Published in: BMC Pediatrics | Issue 1/2019

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Abstract

Background

Insufficient elastin synthesis leads to vascular complications and arterial hypertension in children with Williams-Beuren syndrome. Restoring sufficient quantity of elastin should then result in prevention or inhibition of vascular malformations and improvement in arterial blood pressure.

Methods

The aim of this study was to assess the efficacy and safety of minoxidil on Intima Media Thickness (IMT) on the right common carotid artery after twelve-month treatment in patient with Williams-Beuren syndrome. We performed a randomized placebo controlled double blind trial. All participants were treated for 12 months and followed for 18 months. The principal outcome was assessed by an independent adjudication committee blinded to the allocated treatment groups.

Results

The principal outcome was available for 9 patients in the placebo group and 8 patients in the minoxidil group. After 12-month treatment, the IMT in the minoxidil group increased by 0.03 mm (95% CI -0.002, 0.06) compared with 0.01 mm (95%CI - 0.02, 0.04 mm) in the placebo group (p = 0.4). Two serious adverse events unrelated to the treatment occurred, one in the minoxidil and 1 in the placebo group. After 18 months, the IMT increased by 0.07 mm (95% CI 0.04, 0.10 mm) in the minoxidil compared with 0.01 mm (95% CI -0.02, 0.04 mm) in the placebo group (p = 0.008).

Conclusion

Our results suggest a slight increase after 12 and 18-month follow-up in IMT. More understanding of the biological changes induced by minoxidil should better explain its potential role on elastogenesis in Williams-Beuren syndrome.

Trials registration

US National Institutes of Health Clinical Trial Register (NCT00876200). Registered 3 April 2009 (retrospectively registered).
Appendix
Available only for authorised users
Literature
1.
Williams JC, Barratt-Boyes BG, Lowe JB. Supravalvular aortic stenosis. Circulation. 1961;24:1311–8.CrossRef
2.
Stromme P, Bjornstad PG, Ramstad K. Prevalence estimation of Williams syndrome. J Child Neurol. 2002;17(4):269–71.CrossRef
3.
4.
Gustafson R, Traub D. Williams syndrome: a guide to diagnosis and treatment. S D J Med. 1997;50(3):89–91.PubMed
5.
Mari A, Amati F, Mingarelli R, Giannotti A, Sebastio G, Colloridi V, Novelli G, Dallapiccola B. Analysis of the elastin gene in 60 patients with clinical diagnosis of Williams syndrome. Hum Genet. 1995;96(4):444–8.CrossRef
6.
Morris CA. Genetic aspects of supravalvular aortic stenosis. Curr Opin Cardiol. 1998;13(3):214–9.PubMed
7.
Lacolley P, Boutouyrie P, Glukhova M, Daniel Lamaziere JM, Plouin PF, Bruneval P, Vuong P, Corvol P, Laurent S. Disruption of the elastin gene in adult Williams syndrome is accompanied by a paradoxical reduction in arterial stiffness. Clin Sci (Lond). 2002;103(1):21–9.CrossRef
8.
Collins RT 2nd. Cardiovascular disease in Williams syndrome. Circulation. 2013;127(21):2125–34.CrossRef
9.
Chowdhury T, Reardon W. Elastin mutation and cardiac disease. Pediatr Cardiol. 1999;20(2):103–7.CrossRef
10.
Faury G. Function-structure relationship of elastic arteries in evolution: from microfibrils to elastin and elastic fibres. Pathol Biol (Paris). 2001;49(4):310–25.CrossRef
11.
Goergen CJ, Li HH, Francke U, Taylor CA. Induced chromosome deletion in a Williams-Beuren syndrome mouse model causes cardiovascular abnormalities. J Vasc Res. 2011;48(2):119–29.CrossRef
12.
Faury G, Pezet M, Knutsen RH, Boyle WA, Heximer SP, McLean SE, Minkes RK, Blumer KJ, Kovacs A, Kelly DP, et al. Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency. J Clin Invest. 2003;112(9):1419–28.CrossRef
13.
Shifren A, Durmowicz AG, Knutsen RH, Faury G, Mecham RP. Elastin insufficiency predisposes to elevated pulmonary circulatory pressures through changes in elastic artery structure. J Appl Physiol (1985). 2008;105(5):1610–9.CrossRef
14.
Pezet M, Jacob MP, Escoubet B, Gheduzzi D, Tillet E, Perret P, Huber P, Quaglino D, Vranckx R, Li DY, et al. Elastin haploinsufficiency induces alternative aging processes in the aorta. Rejuvenation Res. 2008;11(1):97–112.CrossRef
15.
Carta L, Wagenseil JE, Knutsen RH, Mariko B, Faury G, Davis EC, Starcher B, Mecham RP, Ramirez F. Discrete contributions of elastic fiber components to arterial development and mechanical compliance. Arterioscler Thromb Vasc Biol. 2009;29(12):2083–9.CrossRef
16.
Campuzano V, Segura-Puimedon M, Terrado V, Sanchez-Rodriguez C, Coustets M, Menacho-Marquez M, Nevado J, Bustelo XR, Francke U, Perez-Jurado LA. Reduction of NADPH-oxidase activity ameliorates the cardiovascular phenotype in a mouse model of Williams-Beuren Syndrome. PLoS Genet. 2012;8(2):e1002458.CrossRef
17.
Lannoy M, Slove S, Jacob MP. The function of elastic fibers in the arteries: beyond elasticity. Pathol Biol (Paris). 2014;62(2):79–83.CrossRef
18.
Li HH, Roy M, Kuscuoglu U, Spencer CM, Halm B, Harrison KC, Bayle JH, Splendore A, Ding F, Meltzer LA, et al. Induced chromosome deletions cause hypersociability and other features of Williams-Beuren syndrome in mice. EMBO Mol Med. 2009;1(1):50–65.CrossRef
19.
Brooke BS, Bayes-Genis A, Li DY. New insights into elastin and vascular disease. Trends Cardiovasc Med. 2003;13(5):176–81.CrossRef
20.
English RF, Colan SD, Kanani PM, Ettedgui JA. Growth of the aorta in children with Williams syndrome: does surgery make a difference? Pediatr Cardiol. 2003;24(6):566–8.CrossRef
21.
Kim YM, Yoo SJ, Choi JY, Kim SH, Bae EJ, Lee YT. Natural course of supravalvar aortic stenosis and peripheral pulmonary arterial stenosis in Williams' syndrome. Cardiol Young. 1999;9(1):37–41.CrossRef
22.
Radford DJ, Pohlner PG. The middle aortic syndrome: an important feature of Williams' syndrome. Cardiol Young. 2000;10(6):597–602.CrossRef
23.
Sadler LS, Pober BR, Grandinetti A, Scheiber D, Fekete G, Sharma AN, Urban Z. Differences by sex in cardiovascular disease in Williams syndrome. J Pediatr. 2001;139(6):849–53.CrossRef
24.
Takeuchi D, Furutani M, Harada Y, Furutani Y, Inai K, Nakanishi T, Matsuoka R. High prevalence of cardiovascular risk factors in children and adolescents with Williams-Beuren syndrome. BMC Pediatr. 2015;15:126.CrossRef
25.
Eronen M, Peippo M, Hiippala A, Raatikka M, Arvio M, Johansson R, Kahkonen M. Cardiovascular manifestations in 75 patients with Williams syndrome. J Med Genet. 2002;39(8):554–8.CrossRef
26.
Nakamoto S, Saga T, Shinohara T. Williams syndrome associated with complete atrioventricular septal defect. Heart. 2003;89(5):e15.CrossRef
27.
Kantharia BK, Mittleman RS. Concomitant reentrant tachycardias from concealed accessory atrioventricular bypass tract and atrioventricular nodal reentry in a patient with Williams syndrome. Cardiology. 1999;91(4):264–7.CrossRef
28.
Rashkind WJ, Golinko R, Arcasoy M. Cardiac findings in idiopathic hypercalcemia of infancy. J Pediatr. 1961;58:464–9.CrossRef
29.
Suarez-Mier MP, Morentin B. Supravalvular aortic stenosis, Williams syndrome and sudden death. A case report. Forensic Sci Int. 1999;106(1):45–53.CrossRef
30.
Bird LM, Billman GF, Lacro RV, Spicer RL, Jariwala LK, Hoyme HE, Zamora-Salinas R, Morris C, Viskochil D, Frikke MJ, et al. Sudden death in Williams syndrome: report of ten cases. J Pediatr. 1996;129(6):926–31.CrossRef
31.
Putman CM, Chaloupka JC, Eklund JE, Fulbright RK. Multifocal intracranial occlusive vasculopathy resulting in stroke: an unusual manifestation of Williams syndrome. AJNR Am J Neuroradiol. 1995;16(7):1536–8.PubMed
32.
Takagi H, Mori Y, Iwata H, Umeda Y, Fukumoto Y, Matsuno Y, Matsutomo M, Shimokawa K, Nishigaki K, Fujiwara H, et al. Mitral regurgitation without supravalvular aortic stenosis in Williams syndrome. Heart Vessels. 2002;16(6):257–9.CrossRef
33.
Bouchireb K, Boyer O, Bonnet D, Brunelle F, Decramer S, Landthaler G, Liutkus A, Niaudet P, Salomon R. Clinical features and management of arterial hypertension in children with Williams-Beuren syndrome. Nephrol Dial Transplant. 2010;25(2):434–8.CrossRef
34.
Wessel A, Motz R, Pankau R, Bursch JH. Arterial hypertension and blood pressure profile in patients with Williams-Beuren syndrome. Z Kardiol. 1997;86(4):251–7.CrossRef
35.
Fleishaker JC, Andreadis NA, Welshman IR, Wright CE 3rd. The pharmacokinetics of 2.5- to 10-mg oral doses of minoxidil in healthy volunteers. J Clin Pharmacol. 1989;29(2):162–7.CrossRef
36.
Strife CF, Quinlan M, Waldo FB, Fryer CJ, Jackson EC, Welch TR, McEnery PT, West CD. Minoxidil for control of acute blood pressure elevation in chronically hypertensive children. Pediatrics. 1986;78(5):861–5.PubMed
37.
Puri HC, Maltz HE, Kaiser BA, Potter DE. Severe hypertension in children with renal disease: treatment with minoxidil. Am J Kidney Dis. 1983;3(1):71–5.CrossRef
38.
Sinaiko AR, O'Dea RF, Mirkin BL. Clinical response of hypertensive children to long-term minoxidil therapy. J Cardiovasc Pharmacol. 1980;2(Suppl 2):S181–8.CrossRef
39.
Pennisi AJ, Takahashi M, Bernstein BH, Singsen BH, Uittenbogaart C, Ettenger RB, Malekzadeh MH, Hanson V, Fine RN. Minoxidil therapy in children with severe hypertension. J Pediatr. 1977;90(5):813–9.CrossRef
40.
Halling SE, Asling-Monemi K, Herthelius M, Celsi G, Vavilis G, Kuru NK, Efvergren M, Krmar RT. Minoxidil therapy in children and young adult patients with renal disease and refractory hypertension: value when multidrug regimens have failed to achieve blood pressure control. J Hum Hypertens. 2010;24(8):552–4.CrossRef
41.
Hayashi A, Suzuki T, Wachi H, Tajima S, Nishikawa T, Murad S, Pinnell SR. Minoxidil stimulates elastin expression in aortic smooth muscle cells. Arch Biochem Biophys. 1994;315(1):137–41.CrossRef
42.
Tajima S. Modulation of elastin expression and cell proliferation in vascular smooth muscle cells in vitro. Keio J Med. 1996;45(1):58–62.CrossRef
43.
Tajima S, Hayashi A, Suzuki T, Nishikawa T. Stimulation of elastin expression by minoxidil in chick skin fibroblasts. Arch Dermatol Res. 1995;287(5):494–7.CrossRef
44.
Tsoporis J, Fields N, Lee RM, Leenen FH. Effects of the arterial vasodilator minoxidil on cardiovascular structure and sympathetic activity in spontaneously hypertensive rats. J Hypertens. 1993;11(12):1337–45.CrossRef
45.
Lannoy M, Slove S, Louedec L, Choqueux C, Journe C, Michel JB, Jacob MP. Inhibition of ERK1/2 phosphorylation: a new strategy to stimulate elastogenesis in the aorta. Hypertension. 2014;64(2):423–30.CrossRef
46.
Aggoun Y, Sidi D, Levy BI, Lyonnet S, Kachaner J, Bonnet D. Mechanical properties of the common carotid artery in Williams syndrome. Heart. 2000;84(3):290–3.CrossRef
47.
Atanasova M, Konova E, Georgieva M, Dimitrova A, Coquand-Gandit M, Faury G, Baydanoff S. Age-related changes of anti-elastin antibodies in senescence-accelerated mice. Gerontology. 2010;56(3):310–8.CrossRef
48.
Kozel BA, Danback JR, Waxler JL, Knutsen RH, de Las Fuentes L, Reusz GS, Kis E, Bhatt AB, Pober BR. Williams syndrome predisposes to vascular stiffness modified by antihypertensive use and copy number changes in NCF1. Hypertension. 2014;63(1):74–9.CrossRef
49.
Milleron O, Arnoult F, Ropers J, Aegerter P, Detaint D, Delorme G, Attias D, Tubach F, Dupuis-Girod S, Plauchu H, et al. Marfan Sartan: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 2015;36(32):2160–6.CrossRef
50.
Slove S, Lannoy M, Behmoaras J, Pezet M, Sloboda N, Lacolley P, Escoubet B, Bujan J, Jacob MP. Potassium channel openers increase aortic elastic fiber formation and reverse the genetically determined elastin deficit in the BN rat. Hypertension. 2013;62(4):794–801.CrossRef
51.
Knutsen RH, Beeman SC, Broekelmann TJ, Liu D, Tsang KM, Kovacs A, Ye L, Danback JR, Watson A, Wardlaw A, et al. Minoxidil improves vascular compliance, restores cerebral blood flow, and alters extracellular matrix gene expression in a model of chronic vascular stiffness. Am J Physiol Heart Circ Physiol. 2018;315(1):H18–32.CrossRef
Metadata
Title
Minoxidil versus placebo in the treatment of arterial wall hypertrophy in children with Williams Beuren Syndrome: a randomized controlled trial
Publication date
01-12-2019
Keyword
Minoxidil
Published in
BMC Pediatrics / Issue 1/2019
Electronic ISSN: 1471-2431
DOI
https://doi.org/10.1186/s12887-019-1544-1

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