Effect of Angiotensine II Receptor Blocker vs. Beta Blocker on Aortic Root Growth in pediatric patients with Marfan Syndrome

Transcription

1 Effect of Angiotensine II Receptor Blocker vs. Beta Blocker on Aortic Root Growth in pediatric patients with Marfan Syndrome Goetz Christoph Mueller University Heart Center Hamburg Paediatric Cardiology

2 Marfan Syndrom Epidemiology autosomal-dominant inheritence men and women affected with same frequency no geographic or ethnic differences Prevalence 1 : : Pathogenesis Defect of microfibril fibrillin-1 Gene: FBN1 Manifestations Cardiovascular: aortic dilatation or dissection, MVP, TVP Skeletal: skoliosis, protrusio acetabuli, pes planus, e.g. Eyes: ectopia lentis, myopia Lung: pneumothorax CNS: dural ectasia Skin: striae distensae

3 Cardiovascular manifestations of Marfan Syndrome 1. Aortic and pulmonary root dilation / aortic aneurysm / aortic dissection 2. Aortic regurgitation 3. Av-valve prolaps 4. Av-valve regurgitation 5. Calcification of mitral annulus are the most important clinical symptoms

4 Cardiovascular manifestations of Marfan Syndrome 1. Aortic and pulmonary root dilation / aneurysm / dissection 2. Aortic regurgitation 3. Av-valve prolaps 4. Av-valve regurgitation 5. Calcification of mitral annulus responsible for morbidity and mortality

5 Aortic aneurysm Aortic dissection Aortic complications resulting in death of up to 50% of undiagnosed and untreated Marfan patients by the age of 40 years

6 Pathophysiologic changes of Aortic wall in MFS degeneration of medial layer dissarray throughout the extracellular matrix shrunken smooth muscle cell thickened basement membranes abnormalities of collagen fibres progressive loss of elastic lamellae Bunton TE, Circ Res 2001; 99:37-43.

7 As reasons for the progressive dilation of aortic root abnormal levels of activation of TGF-ß, a potent stimulator of inflammation and fibrosis, have been found Bee KJ, Ann N Y Acad Sci 2006; 1085:

8 What do we know about the incidence of aortic root aneurysm and dissections in children with Marfan Syndrome?

9 Incidence of aortic aneurysm at time of diagnosis of Marfan Syndrome Mean age at diagnosis 9.0 ± 5.7 years Mueller GC, Ped Card 2013;34:

10 Incidence of aortic aneurysm at time of diagnosis of Marfan Syndrome Mean age at diagnosis 9.0 ± 5.7 years Mueller GC, Ped Card 2013;34:

11 Is there any possibility to stop or slow down aortic dilation in pediatric patients with MFS?

12 Benefit of longterm ß-Blockade in Marfan Syndrome Shores J, N Engl J Med 1994;330:

13 Benefit of longterm ß-Blockade in Marfan Syndrome ß-blocker therapy reduce inotropic and chronotropic hemodynamic stress on aortic wall Shores J, N Engl J Med 1994;330:

14 New treatment option: Angiotensine II Receptor Blocker - reduce hemodynamic stress on aortic wall and inhibit TGF-ß signalling Brooke S, N Engl J Med 2008;358:

15 New treatment option: Angiotensine II Receptor Blocker - reduce hemodynamic stress on aortic wall and inhibit TGF-ß signaling Angiotensine II Receptor Blocker have possibilities to prevent causative aortic wall pathology in Marfan Syndrome. Brooke S, N Engl J Med 2008;358:

16 Less is known about the effect of Angiotensine II Receptor Blocker in pediatric patients with Marfan Syndrome.

17 Study design: - retrospective analysis of 82 pediatric patients with confirmed Marfan Syndrome - in 40 patients treatments by Beta-Blocker or Angiotensine II Rec Blocker were initiated in case of severe or rapid progressive aortic root dilation - analyses of normalized aortic root z-scores before and after treatment initiation were performed - the effect of Beta-Blocker vs. Angiotensine II Rec Blocker on aortic root dilation was compared - in Hamburg Beta-Blocker (n=18) were initiated before 2010 / Angiotensine II Rec Blocker (n=22) were used for all treatment initiations after 2010 Mueller GC, submitted for publication

18 Study population: Angiotensine II Rec Bl N = 22 (13 female) Beta Blocker N = 18 (10 female) p Age at treatment initiation: Gender Follow-up period 10.17± female (59%) 1.40± ± female (56%) 5.51±3.30 p<0.05 ns p<0.01 Aortic root diameter: (before treatment) z-score of aortic annulus z-score of sinus of valsalvae z-score of sinotubular junction 1.13± ± ± ± ± ±0.87 ns p<0.05 p<0.05

19 Rate of change of normalized aortic root diameter under treatment p<0.05 p<0.01 ns ns ns ns Angiotensine II Receptor Blocker (FU 1.40±0.24) Beta-Blocker (FU 5.51±3.30 years)

20 Rate of change of normalized aortic root diameter under treatment p<0.05 p<0.01 ns ns ns ns Angiotensine II Receptor Blocker (FU 1.40±0.24) Beta-Blocker (FU 5.51±3.30 years) no significant difference of aortic root change between the groups

21 Side effects: in the Angiotensine II Receptor Blocker group no significant side effects appeared in the Beta-Blocker group 4 patients switched to Angiotensine II Receptor Blocker in case of side effects (fatigue, dizziness) during follow-up

22 Conclusion: both Angiotensine II Receptor Blocker as well as Beta- Blocker lead to a significant reduction of Sinus of Valsalvae dilation both treatment strategies seem benefical and justified in pediatric patients with Marfan Syndrome

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25 Ausblick und Limitationen both treatment strategies are benefical and justified in pediatric patients with Marfan Syndrome

26 Normalized Sinus of valsalvae z-scores before and after treatment initiation Beta-Blocker (n=18) Angiotensine II Receptor Blocker (n=22) Mueller GC, submitted for publication