EDITORIALS
November 2014 17. Matthew OP, Roberts JL, Thach BT. Pharyngeal airway obstruction in preterm infants during mixed and obstructive apnea. J Pediatr 1982; 100:964-8.
18. Ruggins NR, Milner AD. Site of upper airway obstruction in preterm infants with problematical apnea. Arch Dis Child 1991;66: 787-92.
What Is the Optimal Medical Therapy for Marfan Syndrome?
T
he past 40 years have witnessed astounding progress in BB did better, in both measures, over average follow-up understanding the Marfan syndrome (MFS): what it is, of 7.6 years. This new analysis is important for 3 reasons. what causes it, and how to manage it. Although lifeFirst, several studies suggested a benefit on aortic protecexpectancy was once severely reduced, largely due to cardiotion for ACEI that was superior to BB.10,11 Second, skeptivascular complications, now most affected people can expect cism was expressed about the efficacy of BB in the absence to live a normal life span, if not an uncomof any actual well-controlled trials to supSee related article, p 951 plicated one.1,2 The most important factors port this contrarian view.12 Third, a numin increasing life-expectancy have been heightened awareness ber of new clinical trials comparing BB with ARB therapy of the condition, noninvasive imaging of the heart and the do not involve untreated subjects, so having further data aortic root, and effective prophylactic surgery to replace the on the impact of BB is welcome. dilated ascending aorta, thus preventing acute dissection.3,4 There are a number of shortcomings to this new study. What we call MFS has evolved over the decades: homocystiSo why be interested in nonsurgical therapies? The simple annuria was identified in the 1960s, MASS (mitral valve proswers are to delay the time to elective aortic repair and to lapse, myopia, mild aortic dilatation, striae, skeletal reduce the risk of acute type A dissection while waiting. changes) phenotype in the 1980s, familial thoracic aortic disSeveral approaches are involved in nonsurgical therapy, eases in the 1990s, and Loeys-Dietz syndrome in the 2000s.2 including restrictions on activity (whether occupational or recreational), counseling about and managing the risks of Thus, long-term retrospective investigations of outcomes pregnancy in women with MFS, and drug therapy.5 Thoughts may be biased by inclusion of subjects who were once thought to have MFS, but now no longer would qualify. about pharmacologic therapy arose in the early 1970s, when Furthermore, the most recent diagnostic criteria rely on beta-adrenergic blockade (BB) was first shown to be useful in both phenotype and molecular genetics,13 but most recent the management of acute aortic dissection. At that time, the notion of chronic BB to prevent aortic dissection was quite retrospective and prospective studies have employed older novel and untested in any situation, let alone a rare disorder. criteria. The authors had no way of knowing whether some A randomized, open label study in MFS of propranolol (the of the subjects seen years ago really would qualify for a diagonly drug available in the late 1970s) vs no drug, with subjects nosis of MFS today. Additionally, some of the subjects in the followed for a decade, showed that both the rate of aortic root original report that concluded that ACEI are beneficial were dilatation and the occurrence of aortic complications were from the same institution, but how many and who they were reduced by treatment.6 A number of other medications could not be ascertained.10 Finally, the average dose of BB have been considered for prophylaxis of MFS, either because (0.95 0.63 mg/kg) was actually rather modest, suggesting some patients do not tolerate BB or based on underlying that the dosage was not optimized to, say, reduce postpathophysiology.5,7,8 Calcium channel blockers with negative exercise heart rate. What does the future hold? Considerable insight about inotropic effect, angiotensin converting enzyme inhibitors pathogenesis of aortopathy has emerged from studies of (ACEI), angiotensin receptor blockers (ARB), doxycycline, mice engineered to have MFS. In these animals, which will statins, and others have all been tried in humans or mouse develop aortic aneurysms and dissections, propranolol had models of MFS. some clinical advantage, but no beneficial impact on histopaThe article by Phomakay et al in this issue of The Journal thology of the aortic wall.14 Angiotensin receptor blockade revisits earlier studies, some involving subjects at their own institution, who were treated with ACEI, BB, or nothing, with losartan, however, had a dramatic impact on both aortic but not in a systematic manner.9 Using retrospective data wall structure and outcomes.14 Based on these results, 18 covering 37 years, the authors compared the rate of change young patients with severe MFS who had progressive aortic of aortic dimension and cardiovascular outcomes in 67 padilatation despite BB were treated with ARB and had marked tients. Despite having larger aortic root dimensions at the reduction in the rate of aortic enlargement.15 These outcomes outset of therapy, those patients with MFS treated with in mice and humans led to no less than 10 clinical trials, of varying designs but all involving ARB and BB, to be initiated ACEI ARB BB MFS
Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Beta-adrenergic blockade Marfan syndrome
The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.08.002
889
THE JOURNAL OF PEDIATRICS
www.jpeds.com
around the world. Several of these studies have reported results, which suggest improved aortic protection with ARB therapy.16-18 In the US, a randomized controlled trial comparing atenolol and losartan, each optimally dosed in young patients with MFS, has completed 3-year follow-up in over 600 subjects.19 The results are due to be reported this autumn. A prospective meta-analysis of all of the studies involving ARB treatment is planned. Until these results are conveyed, clinicians should continue to rely on BB as the first-line therapy in patients with MFS and consider substituting an ARB in patients who do not tolerate BB, or adding an ARB when an additional medication is needed for control of blood pressure. The mouse model of MFS has provided recent evidence that ACEI should not be used in humans. The pathogenesis of features in most organ systems involves aberrant signaling through the transforming growth factor beta canonical and noncanonical pathways.20 Inhibiting signaling through the angiotensin II type 1 receptor is protective of the aorta, whereas signaling through the angiotensin II type 2 receptor is also beneficial.20 An ARB inhibits the angiotensin II type I receptor and an ACEI inhibits signaling through both angiotensin II receptors, which is reflected in the benefit of an ARB and not an ACEI in the mouse model. In addition to the pending studies of ARB and BB, there is emerging evidence that calcium channel blockers of all classes are detrimental to the ascending aorta in both mice and humans with MFS (Dietz HC personal communication). Finally, these investigations into the pathogenesis and treatment of aortic disease in MFS may improve our understanding of aortopathy in other syndromes (eg, Turner syndrome, the vascular form of Ehlers-Danlos syndrome, Loeys-Dietz syndrome) and in the many forms of non-syndromic familial thoracic aortic diseases. n Reed E. Pyeritz, MD, PhD Smilow Center for Translational Research Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania Reprint requests: Reed E. Pyeritz, MD, PhD, Smilow Center for Translational Research, 11-133, 3400 Civic Center Blvd, Philadelphia, PA 19104. E-mail: [email protected]
References 1. Pyeritz RE. Marfan syndrome: 30 years of research equals 30 years of additional life expectancy. Heart 2009;95:173-5. 2. Pyeritz RE. Marfan syndrome and related disorders. In: Rimoin DL, Pyeritz RE, Korf BR, eds. Emery and Rimoin’s essential medical genetics. Oxford: Academic Press; 2013. p. 567-74. 3. Gott VL, Greene PS, Alejo DE, Cameron DE, Naftel DC, Miller DC, et al. Surgery for ascending aortic disease in Marfan patients: a multi-center study. N Engl J Med 1999;340:1307-13.
890
Vol. 165, No. 5 4. Coselli JS, Volguina IV, LeMaire SA, Sundt TM, Connolly HM, Stephens EH, et al. Early and 1-year outcomes of aortic root surgery in patients with Marfan syndrome: a prospective, multicenter, comparative study. J Thorac Cardiovasc Surg 2014;147: 1758-66. 5. Keane MG, Pyeritz RE. Medical management of Marfan syndrome. Circulation 2008;117:2802-13. 6. Shores J, Berger KR, Murphy EA, Pyeritz RE. Chronic ß-adrenergic blockade protects the aorta in the Marfan syndrome: a prospective, randomized trial of propranolol. N Engl J Med 1994; 330:1335-41. 7. Rossi-Foulkes R, Roman MJ, Rosen SE, Kramer-Fox R, Ehlers KH, O’Loughlin JE, et al. Phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome. Am J Cardiol 1999;83:1364-8. 8. Ladouceur M, Fermanian C, Lupoglazoff JM, Edouard T, Dulac Y, Acar P, et al. Effect of beta-blockade on ascending aortic dilatation in children with the Marfan syndrome. Am J Cardiol 2007;99: 406-9. 9. Phomakay V, Huett WG, Gossett JM, Tang X, Bornemeier RA, Collins RT II. b-blockers and angiotensin converting enzyme inhibitors: comparison of effects on aortic growth in pediatric patients with Marfan syndrome. J Pediatr 2014;165:951-5. 10. Yetman AT, Bornemeier RA, McCrindle BW. Usefulness of enalapril vs propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol 2005;95:1125-7. 11. Ahimastos AA, Aggarwal A, D’Orsa KM, Formosa MF, White AJ, Savarirayan R, et al. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome. JAMA 2007; 298:1539-47. 12. Tierney ESS, Feingold B, Printz BF, Park SC, Graham D, Lleinman CS, et al. Beta-blocker therapy does not alter the rate of aortic root dilation in pediatric patients with Marfan syndrome. J Pediatr 2007;150: 77-82. 13. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-85. 14. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117-21. 15. Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC III. Angiotensin II blockade and aortic-root dilation in Marfan syndrome. N Engl J Med 2008;358:2787-95. 16. Pees C, Laccone F, Hagl M, DeBrauwer V, Moser E, Michel-Behnke I. Usefulness of losartan on the size of the ascending aorta in an unselected cohort of children, adolescents, and young adults with Marfan syndrome. Am J Cardiol 2013;112:1477-83. 17. Groenink M, den Hartog AW, Franken R, Radonic T, de Waard V, Timmermans J, et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J 2013;34:3491-500. 18. Mueller GC, Stierle L, Stark V, Steiner K, von Kodolitsch Y, Weil J, et al. Retrospective analysis of the effect of angiotensin II receptor blocker vs b-blocker on aortic root growth in pediatric patients with Marfan syndrome. Heart 2014;100:214-8. 19. Lacro RV, Dietz HC, Wruck LM, Bradley TJ, Colan SD, Devereux RB, et al. Rationale and design of a randomized clinical trial of beta blocker therapy (atenolol) vs angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome. Am Heart J 2007; 154:624-31. 20. Habashi JP, Doyle JJ, Holm TM, Aziz H, Schoenhoff F, Bedja D, et al. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science 2011;332:361-4.
November 2014 17. Matthew OP, Roberts JL, Thach BT. Pharyngeal airway obstruction in preterm infants during mixed and obstructive apnea. J Pediatr 1982; 100:964-8.
18. Ruggins NR, Milner AD. Site of upper airway obstruction in preterm infants with problematical apnea. Arch Dis Child 1991;66: 787-92.
What Is the Optimal Medical Therapy for Marfan Syndrome?
T
he past 40 years have witnessed astounding progress in BB did better, in both measures, over average follow-up understanding the Marfan syndrome (MFS): what it is, of 7.6 years. This new analysis is important for 3 reasons. what causes it, and how to manage it. Although lifeFirst, several studies suggested a benefit on aortic protecexpectancy was once severely reduced, largely due to cardiotion for ACEI that was superior to BB.10,11 Second, skeptivascular complications, now most affected people can expect cism was expressed about the efficacy of BB in the absence to live a normal life span, if not an uncomof any actual well-controlled trials to supSee related article, p 951 plicated one.1,2 The most important factors port this contrarian view.12 Third, a numin increasing life-expectancy have been heightened awareness ber of new clinical trials comparing BB with ARB therapy of the condition, noninvasive imaging of the heart and the do not involve untreated subjects, so having further data aortic root, and effective prophylactic surgery to replace the on the impact of BB is welcome. dilated ascending aorta, thus preventing acute dissection.3,4 There are a number of shortcomings to this new study. What we call MFS has evolved over the decades: homocystiSo why be interested in nonsurgical therapies? The simple annuria was identified in the 1960s, MASS (mitral valve proswers are to delay the time to elective aortic repair and to lapse, myopia, mild aortic dilatation, striae, skeletal reduce the risk of acute type A dissection while waiting. changes) phenotype in the 1980s, familial thoracic aortic disSeveral approaches are involved in nonsurgical therapy, eases in the 1990s, and Loeys-Dietz syndrome in the 2000s.2 including restrictions on activity (whether occupational or recreational), counseling about and managing the risks of Thus, long-term retrospective investigations of outcomes pregnancy in women with MFS, and drug therapy.5 Thoughts may be biased by inclusion of subjects who were once thought to have MFS, but now no longer would qualify. about pharmacologic therapy arose in the early 1970s, when Furthermore, the most recent diagnostic criteria rely on beta-adrenergic blockade (BB) was first shown to be useful in both phenotype and molecular genetics,13 but most recent the management of acute aortic dissection. At that time, the notion of chronic BB to prevent aortic dissection was quite retrospective and prospective studies have employed older novel and untested in any situation, let alone a rare disorder. criteria. The authors had no way of knowing whether some A randomized, open label study in MFS of propranolol (the of the subjects seen years ago really would qualify for a diagonly drug available in the late 1970s) vs no drug, with subjects nosis of MFS today. Additionally, some of the subjects in the followed for a decade, showed that both the rate of aortic root original report that concluded that ACEI are beneficial were dilatation and the occurrence of aortic complications were from the same institution, but how many and who they were reduced by treatment.6 A number of other medications could not be ascertained.10 Finally, the average dose of BB have been considered for prophylaxis of MFS, either because (0.95 0.63 mg/kg) was actually rather modest, suggesting some patients do not tolerate BB or based on underlying that the dosage was not optimized to, say, reduce postpathophysiology.5,7,8 Calcium channel blockers with negative exercise heart rate. What does the future hold? Considerable insight about inotropic effect, angiotensin converting enzyme inhibitors pathogenesis of aortopathy has emerged from studies of (ACEI), angiotensin receptor blockers (ARB), doxycycline, mice engineered to have MFS. In these animals, which will statins, and others have all been tried in humans or mouse develop aortic aneurysms and dissections, propranolol had models of MFS. some clinical advantage, but no beneficial impact on histopaThe article by Phomakay et al in this issue of The Journal thology of the aortic wall.14 Angiotensin receptor blockade revisits earlier studies, some involving subjects at their own institution, who were treated with ACEI, BB, or nothing, with losartan, however, had a dramatic impact on both aortic but not in a systematic manner.9 Using retrospective data wall structure and outcomes.14 Based on these results, 18 covering 37 years, the authors compared the rate of change young patients with severe MFS who had progressive aortic of aortic dimension and cardiovascular outcomes in 67 padilatation despite BB were treated with ARB and had marked tients. Despite having larger aortic root dimensions at the reduction in the rate of aortic enlargement.15 These outcomes outset of therapy, those patients with MFS treated with in mice and humans led to no less than 10 clinical trials, of varying designs but all involving ARB and BB, to be initiated ACEI ARB BB MFS
Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Beta-adrenergic blockade Marfan syndrome
The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.08.002
889
THE JOURNAL OF PEDIATRICS
www.jpeds.com
around the world. Several of these studies have reported results, which suggest improved aortic protection with ARB therapy.16-18 In the US, a randomized controlled trial comparing atenolol and losartan, each optimally dosed in young patients with MFS, has completed 3-year follow-up in over 600 subjects.19 The results are due to be reported this autumn. A prospective meta-analysis of all of the studies involving ARB treatment is planned. Until these results are conveyed, clinicians should continue to rely on BB as the first-line therapy in patients with MFS and consider substituting an ARB in patients who do not tolerate BB, or adding an ARB when an additional medication is needed for control of blood pressure. The mouse model of MFS has provided recent evidence that ACEI should not be used in humans. The pathogenesis of features in most organ systems involves aberrant signaling through the transforming growth factor beta canonical and noncanonical pathways.20 Inhibiting signaling through the angiotensin II type 1 receptor is protective of the aorta, whereas signaling through the angiotensin II type 2 receptor is also beneficial.20 An ARB inhibits the angiotensin II type I receptor and an ACEI inhibits signaling through both angiotensin II receptors, which is reflected in the benefit of an ARB and not an ACEI in the mouse model. In addition to the pending studies of ARB and BB, there is emerging evidence that calcium channel blockers of all classes are detrimental to the ascending aorta in both mice and humans with MFS (Dietz HC personal communication). Finally, these investigations into the pathogenesis and treatment of aortic disease in MFS may improve our understanding of aortopathy in other syndromes (eg, Turner syndrome, the vascular form of Ehlers-Danlos syndrome, Loeys-Dietz syndrome) and in the many forms of non-syndromic familial thoracic aortic diseases. n Reed E. Pyeritz, MD, PhD Smilow Center for Translational Research Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania Reprint requests: Reed E. Pyeritz, MD, PhD, Smilow Center for Translational Research, 11-133, 3400 Civic Center Blvd, Philadelphia, PA 19104. E-mail: [email protected]
References 1. Pyeritz RE. Marfan syndrome: 30 years of research equals 30 years of additional life expectancy. Heart 2009;95:173-5. 2. Pyeritz RE. Marfan syndrome and related disorders. In: Rimoin DL, Pyeritz RE, Korf BR, eds. Emery and Rimoin’s essential medical genetics. Oxford: Academic Press; 2013. p. 567-74. 3. Gott VL, Greene PS, Alejo DE, Cameron DE, Naftel DC, Miller DC, et al. Surgery for ascending aortic disease in Marfan patients: a multi-center study. N Engl J Med 1999;340:1307-13.
890
Vol. 165, No. 5 4. Coselli JS, Volguina IV, LeMaire SA, Sundt TM, Connolly HM, Stephens EH, et al. Early and 1-year outcomes of aortic root surgery in patients with Marfan syndrome: a prospective, multicenter, comparative study. J Thorac Cardiovasc Surg 2014;147: 1758-66. 5. Keane MG, Pyeritz RE. Medical management of Marfan syndrome. Circulation 2008;117:2802-13. 6. Shores J, Berger KR, Murphy EA, Pyeritz RE. Chronic ß-adrenergic blockade protects the aorta in the Marfan syndrome: a prospective, randomized trial of propranolol. N Engl J Med 1994; 330:1335-41. 7. Rossi-Foulkes R, Roman MJ, Rosen SE, Kramer-Fox R, Ehlers KH, O’Loughlin JE, et al. Phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome. Am J Cardiol 1999;83:1364-8. 8. Ladouceur M, Fermanian C, Lupoglazoff JM, Edouard T, Dulac Y, Acar P, et al. Effect of beta-blockade on ascending aortic dilatation in children with the Marfan syndrome. Am J Cardiol 2007;99: 406-9. 9. Phomakay V, Huett WG, Gossett JM, Tang X, Bornemeier RA, Collins RT II. b-blockers and angiotensin converting enzyme inhibitors: comparison of effects on aortic growth in pediatric patients with Marfan syndrome. J Pediatr 2014;165:951-5. 10. Yetman AT, Bornemeier RA, McCrindle BW. Usefulness of enalapril vs propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol 2005;95:1125-7. 11. Ahimastos AA, Aggarwal A, D’Orsa KM, Formosa MF, White AJ, Savarirayan R, et al. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome. JAMA 2007; 298:1539-47. 12. Tierney ESS, Feingold B, Printz BF, Park SC, Graham D, Lleinman CS, et al. Beta-blocker therapy does not alter the rate of aortic root dilation in pediatric patients with Marfan syndrome. J Pediatr 2007;150: 77-82. 13. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-85. 14. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117-21. 15. Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC III. Angiotensin II blockade and aortic-root dilation in Marfan syndrome. N Engl J Med 2008;358:2787-95. 16. Pees C, Laccone F, Hagl M, DeBrauwer V, Moser E, Michel-Behnke I. Usefulness of losartan on the size of the ascending aorta in an unselected cohort of children, adolescents, and young adults with Marfan syndrome. Am J Cardiol 2013;112:1477-83. 17. Groenink M, den Hartog AW, Franken R, Radonic T, de Waard V, Timmermans J, et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J 2013;34:3491-500. 18. Mueller GC, Stierle L, Stark V, Steiner K, von Kodolitsch Y, Weil J, et al. Retrospective analysis of the effect of angiotensin II receptor blocker vs b-blocker on aortic root growth in pediatric patients with Marfan syndrome. Heart 2014;100:214-8. 19. Lacro RV, Dietz HC, Wruck LM, Bradley TJ, Colan SD, Devereux RB, et al. Rationale and design of a randomized clinical trial of beta blocker therapy (atenolol) vs angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome. Am Heart J 2007; 154:624-31. 20. Habashi JP, Doyle JJ, Holm TM, Aziz H, Schoenhoff F, Bedja D, et al. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science 2011;332:361-4.
