Arterial-Ventriculo-Atrial Interaction in Patients After Surgical Repair of Coarctation of the Aorta

Professor Cheung, Yiu Fai   (Principal Investigator)

18

2013-06-01

80000

Arterial-Ventriculo-Atrial Interaction in Patients After Surgical Repair of Coarctation of the Aorta

arterial function, atrial mechanics, coarctation of aorta, microRNA, ventricular mechanics

Cardiovascular Research

201209176044

Small Project Funding

2012

Completed

Surgical repair of coarctation of the aorta (CoA) has significantly improved the survival of infants and children with this common congenital heart condition. Nonetheless, long-term complications remain an issue of concern despite apparently ‘successful’ repair. Life expectancy in adult patients with repaired CoA are shorter compared with the general population. Systemic hypertension has been reported to occur at a prevalence of 30% and more in patients aged 15 and above. Common causes of death in long-term survivors are primarily cardiovascular in aetiology, and include coronary artery disease, heart failure, and cerebrovascular accidents. The mechanisms underlying the increased cardiovascular risk remain unclear. Abnormal left ventricular (LV) geometry, hypertrophy of the myocardium, and myocardial fibrosis have been documented after CoA repair. Conventional echocardiographic assessments of LV function in these patients have, however, been limited to indirect M-mode assessment of changes in cavity dimensions rather than direct evaluation of myocardial performance. The apparently normal or ‘supranormal’ LV systolic function reported using conventional echocardiographic assessment may be artifactual, in part being confounded by the presence of LV myocardial hypertrophy. The LV mechanics as determined by direct interrogation of myocardial deformation long term after CoA repair are poorly defined. Notwithstanding, advances in myocardial deformation imaging technology by speckle tracking echocardiography have enabled evaluation of myocardial strain and strain rate in three-dimensions and LV torsion in other types of congenital and acquired heart diseases in the young, and shown promise in the detection of subclinical myocardial dysfunction. Apart from intrinsic LV properties, performance of the left ventricle depends also on its preload and afterload. The left atrial (LA) function plays an important role in LV diastolic filling and the intrinsic LV diastolic properties in turn also influence atrial function. The left atrium achieves its role via its reservoir, conduit, and pump function. The LA size or volume is also increasingly recognized as a predictor for cardiovascular outcomes. Whether LA function is altered in patients after CoA repair and its interaction of LV performance have hitherto not been explored. With regard to afterload, alterations in vascular phenotypes in repaired CoA patients have been reported. In these patients, structural alterations in terms of increased collagen content and carotid intima-media thickness and functional disturbances with reduced arterial reactivity and increased arterial stiffness in pre-coarctation arterial segments have been documented. Hence, it appears probable that arterial-ventriculo-atrial interaction may play an important role in determining global LV performance in the long-term after CoA repair, a novel concept that has not been explored to date, and may have implications on long-term increased cardiovascular risk. While the morphological and functional disturbances of LV remodeling in CoA despite repair have been the focus in previous studies as aforementioned, the molecular regulatory mechanism of LV remodeling in after repair of CoA is undefined. Recent studies have unveiled a potentially important role of microRNAs (miRNA), a class of small non-coding RNAs, in the control of diverse aspects of cardiac function, modulation of cardiac remodeling, and pathogenesis of cardiovascular diseases. miRNAs are highly conserved noncoding RNAs that negatively regulate the expression of mRNA through translational repression or mRNA degradation. While initial studies have focused on tissue-based assessment of miRNA expression and quantification, recent studies have shown that miRNAs are also released into the blood stream with marked biostability, and are measurable in serum and plasma with high sensitivity and specificity. In patients with cardiac damage due to acute myocardial infarction, increase in circulating levels of miR-1, miR-133a, miR-208a, miR-208b, and miR-499 have been reported. Of relevance to CoA, which is associated with myocardial hypertrophy and fibrosis, is the demonstration of the role of miR-1, miR 133, and miR-208a in the development of ventricular hypertrophy, and miR-21 and miR-29 in the development of cardiac fibrosis. The primary objectives of the proposed study are 1) to test the hypothesis that LV deformation is altered in patients long-term after repair of CoA 2) to determine its relationship with LA and arterial mechanics, and 3) to explore potential alteration in circulating levels of heart-related miRNAs in patients and their relationship with indices of myocardial damage and function. The issues to be addressed in this study are: i) resting and exercise-stressed LV and LA myocardial mechanics and their inter-relationships, ii) arterial function and its relationship to LV function and LA function iii) LV contractile reserve during exercise stress, and iv) levels of circulating heart-related miRNAs and their relationship to cardiac troponin T as determined using a high sensitivity assay (hs-cTnT) and LV myocardial deformation