Abstract 2958: Perindopril Reduces Large Artery Stiffness and Left Ventricular Outflow Tract Diameter in Patients with Marfan syndrome

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Introduction: Aortic stiffness is elevated in Marfan syndrome (MFS) contributing to aortic dilatation and rupture, the major cause of premature death in this population. Excessive signalling by the transforming growth factor-β(TGFβ) plays a crucial role in the development of aortic dilatation. Hypothesis: Given the known beneficial effects of angiotensin converting enzyme (ACE) inhibitors on arterial stiffness, we hypothesised that perindopril therapy would reduce aortic stiffness and attenuate aortic dilatation in MFS patients, possibly through effects on TGFβ signalling. Methods: 17 MFS patients (aged 33 ± 5) on standard β-blocker therapy were randomised to also receive 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 central (PWVc) and peripheral (PWVp) pulse wave velocity. Left ventricular outflow tract (LVOT) diameter was assessed via a transthoracic echocardiogram. Venous blood samples were analysed for latent and active TGFβ levels using ELISA. 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). In addition, perindopril significantly reduced LVOT diameter (perindopril -2.8 ± 0.4mm vs placebo 1.1 ± 0.3mm, p<0.0001). While perindopril marginally reduced mean arterial blood pressure (perindopril -1.3 ± 0.2mmHg vs placebo 0.2 ± 0.5mmHg, 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 blood pressure was included as a covariate. Finally, perindopril reduced latent TGFβ levels by -14.0 ± 4.5ng/ml when compared to placebo (2.0 ± 2.3ng/ml, p=0.01), and active TGFβ levels by -4 ± 1ng/ml (placebo 3 ± 1 ng/ml, p=0.02). Conclusions: In conclusion, ACE inhibition reduces aortic stiffness and LVOT diameter in MFS patients possibly through attenuation of TGFβsignalling, and may potentially protect against aortic rupture.

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