Circulating MicroRNA and Right Ventricular Function in Patients After Repair of Tetralogy of Fallot

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

Dr Ng Enders Kai On   (Co-Investigator)

Dr Kwong Ava   (Co-Investigator)

24

2011-02-01

41016

Circulating MicroRNA and Right Ventricular Function in Patients After Repair of Tetralogy of Fallot

microRNA, tetralogy of Fallot, ventricular function

Cardiovascular Research

201007176222

Small Project Funding

2010

Completed

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Surgical correction of this structural cardiac defect is accomplished by closure of the ventricular septal defect, resection of infundibular muscle, and commonly transannular patch enlargement of the right ventricular (RV) outflow. The pulmonary valve is rendered incompetent by transannular incision and RV dilation is a usual encounter after TOF repair. Importantly, significant RV dilation due to severe chronic pulmonary regurgitation is associated with systolic and diastolic ventricular dysfunction, ventricular arrhythmias, and impairment of exercise capacity. Serial evaluation of RV function is hence of paramount importance in the follow-up of the growing populating of adolescent and adult patients after TOF repair and decision of the need and timing of pulmonary valve replacement. While echocardiography has been the mainstay of assessment, the evaluation in postoperative TOF patients has been limited by difficult acoustic windows of imaging and complex geometry of the right ventricle that precludes the use of geometric assumptions. Cardiac magnetic resonance imaging may offer superior imaging quality independent of geometric assumption but has been limited by cost and inconvenient access. On the other hand, circulating biomarkers have increasingly been explored for possible diagnosis, monitoring, and prognostication of left heart failure in adults with ischaemic and non-ischaemic heart diseases. Additionally, the biomarkers may provide insight into potential pathogenic mechanisms that underlie the development and progression of heart failure. Recent studies have unveiled a potentially important role of a class of small non-coding RNAs, known as microRNAs (miRNAs), in the control of diverse aspects of cardiac function, modulation of different processes of cardiac remodeling, and pathogenesis of cardiovascular diseases. miRNAs are highly conserved noncoding RNAs that pair with specific target mRNAs and negatively regulate their expression through translational repression or mRNA degradation. In determining the potential role of RNAs in heart failure, earlier studies have examined and reported profiles of differential tissue miRNA expression in human and experimental models of heart failure. Further studies have provided evidence of involvement of selective miRNAs in myocardial hypertrophy, regulation of cardiac apoptosis, regulation of cytoskeleton of cardiomyocytes and cardiac extracellular matrix, and neurohormonal activation, all of which contribute to adverse cardiac remodeling and hence possibly progressive heart failure. While initial studies have focused on tissue-based assessment of miRNA expression and quantification, recent studies have shown that microRNAs are also released into the blood stream and measurable in serum and plasma. Indeed, encouraging data on microRNAs being biomarkers for diagnosis and risk stratification have been increasingly reported in the cancer literature. Data on the potential use of microRNAs as novel myocardial biomarkers has also recently been reported. In an animal model and human subjects, elevation of the cardiac specific miRNA-208a has been shown to be a potentially useful for early diagnosis of myocardial infarction. Another recent study has further shown elevation of six miRNAs in adults with clinical heart failure. In particular, miR423-5p has been shown to be specifically enriched in the blood of heart failure patients and not in patients with non-heart failure related dyspnoea, and receiver-operator-characteristics curve analysis showed miR423-5p to be a diagnostic predictor of heart failure. These encouraging data, albeit limited to date, provide the evidence that circulating miRNAs are potential candidate biomarkers of cardiac function in perhaps not only acquired but also congenital heart diseases. Given the chronically altered loading condition, myocardial dysfunction, and fibrosis of the right ventricle after TOF repair and the increasingly unveiled potential roles of microRNA in myocardial dysfunction and fibrosis, we hypothesize that the expression profile of circulating miRNAs is altered in patients after surgical repair of TOF and may reflect RV function. The proposed study is, to our knowledge, the first to explore the potential significance of circulating microRNA in evaluating RV dysfunction. The primary objective of the present study is to test the hypothesis that the expression profile of circulating miRNAs is altered in patients after surgical repair of TOF compared with healthy subjects. The issues to be addressed in the proposed study include the followings: i) to determine the expression pattern of serum miRNAs in patients after TOF repair compared with healthy control subjects, ii) to assess the relationship between RV volume load and serum levels of microRNA markers, iii) to assess the relationship between indices of RV function as assessed by echocardiography and cardiac magnetic resonance imaging and serum levels of microRNA markers, and iv) to evaluate the use of miRNAs in discriminating patients with from those without RV systolic dysfunction.