A novel integrated approach to the pathogenetic question of ascending aortic disease with congenital bicuspid aortic valve


People involved: Alberto Redaelli, Emiliano Votta, Carlo Conti, Marco Stevanella, Alessandra Pelosi

Funding source: Italian Research Ministry Grant

Grant number: PRIN-2006-063487

Funding period: 2006 - 2008

Partners: Department of Cardio-thoracic and Respiratory Sciences, Second University of Naples, Monaldi Hospital, Naples; Biomorfological and Functional Science Department, Federico II University, Naples.

Congenital bicuspid aortic valve, the most frequent cardiac malformation (1-2% of all live birth) is known to be a predisposing factor for development of ascending aortic dilative disease. An ascending dilatation or aneurysm has been found in as much as 50-70% of adult patients with a bicuspid aortic valve (BAV). Despite this relevant epidemiology, the pathogenesis of aortic dilatation associated to BAV has still to be elucidated. Two opposite theories have been proposed: a "genetic" theory, attributing both valve malformation and aortic intrinsic weakness to a common inherited developmental defect, and a "hemodynamic" theory, attributing a central role to flow derangements caused by valve dysfunction (post-stenotic mechanism). A precise mechanisms of inheritability has not been discovered, nor an underlying genetic defect has been detected, and the genetic theory seems to be limited by the evidence of BAV subjects not developing aortic dilation. On the other side, the hemodynamic theory is contrasted by the evidence of aortic dilatations in BAV subjects without stenosis or with a mild degree stenosis. To clarify pathogenetic aspects of this matter could prelude to the development of preventive or therapeutic strategies. In particular, the scope to more deeply discriminate the role of hemodynamic disturbances, representing a more feasibly addressable factor for medical or surgical interventions compared to genetic anomalies, has not been undertaken in previous studies.
To this purpose, the present inter-university research program will employ a multidisciplinary approach, integrating the most up-to-date knowledge and the most forefront methods and technologies both in the field of flow analysis in biological structures, both in that of bio-morphology and microstructure and in clinical practice of epidemiology (study of risk factors) diagnosis and treatment. The objectives of this project will include:
1) a clinical-epidemiological study, aiming to find the risk factors in patients with BAV for developing aortic dilatation, to characterize subpopulations of BAV patients with respect to the risk of being affected by different forms of aortic disease and to analyse the relations between valve dysfunction and ascending aorta dilatation;
2) a qualitative and quantitative assessment of flow patterns in the aorta downstream from a bicuspid valve, using "time-resolved phase-contrast magnetic resonance velocity mapping" methods;
3) a simulation in mathematical models (finite element models) of the biomechanical stimuli acting on the ascending aortic wall of subjects with BAV, trying to develop both paradigmatic and patient-specific models;
4) an investigation on the microstructural changes in the medial layer of the ascending aortic wall in patients with BAV disease, comparing them to those observed in tricuspid aortic valve disease, focusing on the cellular (apoptosis, anoikis, phenotype shift) and extracellular (protease production, basal lamina changes) phenomena of "flow-induced vascular remodeling": the possibility of an analysis of the spatial distribution of morphological changes in the light of the geometrical patterns of rheology abnormalities will be verified.