Neo-Aortic Root Stiffness following Arterial Switch Operation: Relationship with Neo-Aortic Root Dilatation and Regurgitation

Professor Cheung, Yiu Fai   (Principal Investigator (PI))

Dr Chen Robin   (Co-Investigator)

18

2012-05-01

80000

Neo-Aortic Root Stiffness following Arterial Switch Operation: Relationship with Neo-Aortic Root Dilatation and Regurgitation

aortic stiffness, arterial switch operation

Cardiovascular Research

201109176026

Small Project Funding

2011

Completed

In complete transposition of the great arteries (TGA), the aorta arises from the right ventricle while the pulmonary trunk arises from the left ventricle. Arterial switch operation (ASO) enables complete anatomic correction of this common cyanotic heart defect and is the surgery of choice in the present era. While restoring anatomic connection between the left ventricle and the neoaorta and having a satisfactory survival rate, ASO has been associated with neo-aortic root dilatation and regurgitation, which are issues of concern in the long-term. The mechanisms of late neoaortic complications after ASO for complete TGA remain, however, unclear. Histological abnormalities of the great arteries have been documented in patients with TGA. Intra-operative biopsies of the ascending aorta show medial abnormalities that include the loss of elastic fibres and smooth muscles and increased ground substance and collagen. These histological changes may be functionally manifested by arterial stiffening, which may potentially lead to progressive neoaortic dilation and left ventricular dysfunction. Nonetheless, data on neo-aortic stiffening, its predisposing genetic and non-genetic risk factors, and its functional implications on aortic dimensions and left ventricular function in patients with complete TGA after ASO patients are limited. With regard to possible genetic factors, the contributory role of genetic variations in extracellular matrix proteins and their homeostasis to arterial stiffening is of potential relevance. Matrix metalloproteinases (MMPs) are capable of degrading extracellular matrix proteins including elastin and collagen, which are important determinants of arterial stiffness. In healthy adults, polymorphisms of MMP-3 and MMP-9 have been associated with arterial stiffening. The influence of genetic and non-genetic factors on aortic mechanics in post ASO patients remains, however, to be defined. An important consequence of arterial stiffening is increase in central aortic pressure. Importantly, both arterial stiffness and central blood pressure (BP) has been shown to be associated with and predict independently occurrence of cardiovascular morbidities and mortalities. Technological advancement has enabled non-invasive assessment of arterial stiffness and estimation of central blood pressure. The use of radial artery waveform in the assessment of central BP has been validated and indices generated from radial artery waveform analysis including central systolic BP, central pulse pressure, and radial augmentation index (rAI) have been shown to be independent risk factors for occurrences of adverse cardiovascular events. Additionally, measurement of carotid-femoral pulse wave velocity (PWV) enables assessment of the regional stiffness of the entire aorta. In TGA patients after ASO, possible perturbation of the central arterial mechanics has hitherto not been explored. To date, assessment of arterial mechanics in patients with congenital heart defects including those with complete TGA has been limited to evaluation at the baseline resting state. It is worthwhile noting, however, that BP response to exercise may also be a cardiovascular risk factor. Individuals with normal resting BP but with exaggerated BP response during exercises stress have been shown to be at risk of developing hypertension and other adverse cardiovascular events compared with those having a normal response. Based on the Framingham Heart Study, the exercise diastolic blood pressure has been associated with occurrence of cardiovascular disease. With histological documentation of aortic medial abnormalities in patients with complete TGA, exaggerated BP response and changes of arterial stiffness during exercise stress in patients after ASO might have implications of development of neo-aortic root dilation and regurgitation. Given the histological abnormalities of elastin disruption and increased collagen in the aorta in TGA, we hypothesize that neo-aortic stiffness is increased in the long-term in TGA patients after ASO and associated with neo-aortic root dilatation, neo-aortic valve regurgitation and left ventricular dysfunction. The proposed study is, to our knowledge the first to systemic evaluate the implications of aortic mechanics on neoaortic dilation and left ventricular dysfunction in TGA patients late after anatomic repair. The primary objective of the proposed study is to test the hypothesis that neoaortic stiffness in increased in patients with complete TGA after ASO compared with healthy controls. Additional issues to be addressed in the proposed study including the followings: i) demographic and clinical factors associated with neoaortic stiffness after ASO, ii) potential modulating effects of MMP-3 and MMP-9 polymorphisms on neoaortic root stiffness and dilation after ASO, iii) influence of neoaortic stiffness and other central aortic haemodynamic parameters on neoaortic root dilation and regurgitation, and iv) influence of the neoaortic stiffness and left ventricular systolic and diastolic function