Authors:
A.A. Ahimastos¹, A. Aggarwal², K.M. D'orsa¹, M. Formosa¹, A.J. White¹, R. Savarirayan², A.M. Dart¹, B.A. Kingwell¹, ¹Baker Heart Research Institute - Melbourne - Australia, ²Royal Melbourne Hospital - Melbourne - Australia,

Objectives: Aortic stiffness is elevated in Marfan syndrome (MFS) contributing to aortic dilatation and rupture, the major cause of premature death in this population. We have shown that the ACE inhibitor perindopril reduced arterial stiffness by 60% and left ventricular outflow tract (LVOT) diameter by 3mm in MFS patients (p<0.0001). Excessive signalling by the transforming growth factor-β (TGF-β) family of cytokines is believed to play a crucial role in the development of aortic dilatation. We hypothesised that reduction in LVOT diameter would correlate with reduction in plasma TGF-β levels.

Methods: 17 MFS patients (aged 33±5 (mean±SD)) on standard β-blocker therapy were randomised to also receive either perindopril (8mg od, n=10) or placebo (n=7) for 24 weeks in a double blind study. Indices of arterial stiffness were assessed globally via systemic arterial compliance (SAC) and augmentation index (AIx), and regionally via carotid-femoral (PWVc) and femoral-dorsalis pedis (PWVp) pulse wave velocity. LVOT diameter was assessed via a transthoracic echocardiogram. Venous blood samples were analysed for latent and active TGF-β levels using ELISA. Data are expressed as percent or absolute change from baseline for the placebo and perindopril groups.

Results: Perindopril reduced arterial stiffness as indicated by increased SAC (perindopril 62±11% vs placebo -4.30±1%, p<0.0001), reduced AIx (perindopril -23.50±3% vs placebo 3±1%, p<0.0001), reduced PWVc (perindopril -21±2% vs placebo 5±2%, p<0.0001) and PWVp (perindopril -20±2% vs placebo 2±1%, p<0.0001). Perindopril significantly reduced LVOT diameter (perindopril -2.8±0.4 mm vs placebo 1.1±0.3 mm, p<0.0001). While perindopril marginally reduced mean arterial blood pressure (perindopril -1.3±0.2 mmHg vs placebo 0.2±0.5 mmHg, p=0.004), importantly, the observed changes in both stiffness (p=0.001-0.006) and LVOT diameter (p<0.001) remained significant when mean arterial blood pressure was included as a covariate. Perindopril reduced latent TGF-β levels by -14.0±4.5 ng/ml when compared to placebo (2.0±2.3 ng/ml, p=0.01), and active TGF-β levels by -4±1 ng/ml (placebo, 3±1 ng/ml, p=0.02). There were moderately strong correlations between the pre/post intervention change in LVOT diameter and the change in both latent and active TGF-β levels (latent TGF-β, r=0.49, p=0.04; active TGF-β, r=0.74, p=0.002).

Conclusions: ACE inhibition reduced aortic stiffness and LVOT diameter in MFS patients possibly through attenuation of TGF-β signalling. Plasma TGF-β could be a useful prognostic indicator of progression of aortic dilatation and response to therapy in MFS.