Paediatrics (RCH) - Theses
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ItemEnd-organ consequences of the Fontan circulation( 2022)The Fontan procedure is the last in a series of staged surgical procedures offered to children born with complex congenital heart disease in whom a two-ventricle repair is not feasible. Since its first description, the Fontan procedure has undergone a number of technical modifications which have further improved survival and reduced associated morbidity. Due to improved survival, the number of people living with a Fontan circulation is growing, and the average age is increasing. However, with more patients surviving into adulthood we are unfortunately seeing that many will develop complications. Ventricular dysfunction, circulatory failure, atrioventricular valve (AVV) regurgitation, cardiac arrhythmias, protein-losing enteropathy, plastic bronchitis and thromboembolic phenomena have all been increasingly recognized as potential complications after the Fontan operation. Hepatic fibrosis, cirrhosis and hepatocellular carcinoma have also been described, as well as renal dysfunction in the form of reduced glomerular filtration rate (GFR) and microalbuminuria. The aim of this thesis was to (i) characterize the prevalence and severity of hepatic and renal complications in patients with a Fontan circulation, (ii) identify potential risk factors that may contribute to the development of hepatic and renal complications after the Fontan procedure, and (iii) inform screening practices for end-organ complications in these patients. In this thesis I have demonstrated that: (i) the majority of patients with a Fontan circulation have non-invasive evidence of liver fibrosis by early adulthood, (ii) a smaller but significant proportion of patients will be diagnosed with liver cirrhosis by early adulthood, (iii) a minority of patients will develop hepatocellular carcinoma, which may occur in adolescence or early adulthood, (iv) history of cardiac arrhythmia or AVV failure is associated with an increased risk of advanced liver disease, (v) mild renal dysfunction is common in patients with a Fontan circulation, however, does not appear to negatively impact mid-term outcomes, (vi) creatinine based estimated GFR should be interpreted with caution in children with a Fontan circulation, and tends to over-estimate true or measured GFR in children and adults with a Fontan circulation, (vii) many of the patients who were found to have hepatic or renal dysfunction were identified on routine screening. This thesis has drawn attention to the significant proportion of patients with a Fontan circulation who will develop hepatic or renal dysfunction during long-term follow-up. These findings encourage us to consider the implications of end-organ dysfunction on the medical management of a population that is growing in numbers and age. This work emphasizes the importance of routine surveillance in identifying those with significant liver and kidney dysfunction after the Fontan procedure, and identifies a number of potentially modifiable risk factors for more advanced disease. In the absence of any proven pharmacological treatment for these complications, it is likely that optimisation of the Fontan circulation itself in combination with the avoidance of secondary end-organ insults will be the key to minimising the burden of hepatic and renal disease in this population.
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ItemLong-term outcomes of truncus arteriosus repair( 2020)Truncus arteriosus is a rare congenital cardiac defect which results in a single common arterial trunk exiting the heart which supplies the systemic, pulmonary, and coronary circulations. The truncus itself is guarded by a single, often large common valve – the truncal valve – which separates the truncus from both the left and right ventricle. Truncus arteriosus has an incidence of 3 to 10 per 100,000 live births. Although only 0.7% – 3% of all congenital cardiac anomalies are due to truncus arteriosus, it accounts for 4% of all critical congenital cardiac anomalies. Patients typically present early in life with symptoms of cyanosis and congestive cardiac failure. Nowadays, surgery is undertaken early in life prior to the development of irreversible pulmonary hypertension. Improvements in surgical techniques and perioperative management has drastically reduced early mortality to 3 – 20%. Therefore, many children who have undergone truncus arteriosus repair are living well into adulthood. Despite this, there are few large studies addressing the long-term outcomes of truncus arteriosus repair. Furthermore, the impact of concomitant anomalies and the truncal valve are insufficiently described. This Doctor of Philosophy focuses on the long-term outcomes of truncus arteriosus repair in order to determine the current results and risk factors for poor outcomes. This research constitutes the largest single-institutional and multi-institutional experience assessing the long-term outcomes of truncus arteriosus repair with the longest follow-up time. I demonstrated that the majority of mortality following truncus arteriosus repair occurs within the first year after repair, and survival beyond the first year is excellent. I found that the presence of a coronary artery anomaly was associated with both early and late mortality and suggest that the coronary anatomy be clearly identified intraoperatively. Furthermore, patients with DiGeorge syndrome are at risk of late mortality, most commonly due to infection. Interestingly, I found that patients with mild or less truncal valve insufficiency are free from truncal valve surgery for up to 25 years, despite their truncal valve anatomy. In contrast, most patients with moderate or greater truncal valve insufficiency – particularly those with a quadricuspid truncal valve – will require truncal valve surgery at some stage in their lifetime. Of note however, the durability of truncal valve repair as a whole is poor, with most patients requiring reoperation on the truncal valve. In those with a quadricuspid truncal valve, repair by tricuspidization appears to be the most durable option with good long-term outcomes. Tricuspidization provided better long-term outcomes even if the non-tricuspidization group included younger children (less than 6 years of age), in whom truncal valve replacement was performed. This is an important finding as it suggests that younger children may benefit from truncal valve repair rather than a replacement with a smaller (non-adult sized) mechanical prosthesis which may require repeat replacement. Furthermore, if repair of the truncal valve is possible, this would avoid life-long anti-coagulation and the associated risks. In the long-term, patients had an excellent functional status following truncus arteriosus repair but had a high rate of reoperation due to the use of a conduit for reconstruction of the right ventricular outflow tract. Despite the high reoperation rate, patients have similar quality of life compared to age-matched Australian controls. This Doctor of Philosophy has redefined our understanding of the long-term outcomes of truncus arteriosus repair. The findings presented will impact clinical decision making, and I envision an improvement in the outcomes of these rare and complex patients.
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ItemNon-invasive arterial wave analysis in congenital heart disease( 2018)Elevated large arterial stiffness is an independent risk factor for adult cardiovascular and cerebrovascular disease. Arterial dysfunction may already be evident in childhood, and children born preterm, or with a history of congenital cardiac surgery, particularly coarctation of the aorta, have a high burden of adult cardiovascular disease and hypertension. Novel arterial wave analyses such as Wave Intensity (WI) and Wave Power (WP) assess the interaction between the heart and great vessels, providing insights into mechanisms of hypertension. Non-invasive WI/WP analyses rely on accurate acquisition of velocity (U), and diameter (D) with ultrasound. Although ultrasound methods are well suited to measuring peak U, WI/WP rely on mean U, which is difficult to obtain routinely. Local pulse-wave speed (c), a measure of arterial stiffness, can also be determined by constructing PU or ln(D)U loops, which also rely on mean U. Errors in c with PU and ln(D)U loop methods due to inaccurate U were determined using MRI-based verification and simulated virtual cohort. A novel method for acquiring local c, which accounts for errors in U and those related to proximal wave reflections, was developed. This technique allowed for scaling factors to be derived to convert peak U into mean U, enabling WI/WP analysis using widely available clinical equipment. In an animal model, invasive and non-invasive WI/WP analyses were compared. The correlations for WI and WP indices were good, but agreement was poor- with a majority of the bias accounted for by either inaccurate invasive U or non-invasive flow estimation, and to non-invasive underestimation of peak P rates of change. Agreement and correlation for wave-related pressure changes were acceptable, and non-invasive WI analysis detected similar relative changes in wave indices during haemodynamic perturbations. Ex-preterm adolescents born at <28 weeks gestation and largely at appropriate weight for gestational age were found to have elevated systolic blood pressure, with no difference in conventional vascular indices. They had a smaller ascending aorta and greater wave reflection on non-invasive WI assessed in the aorta, which was associated with systolic blood pressure on multivariable analysis. Non-invasive WI/WP was also applied in a study of young adults after coarctation repair. They had higher aortic stiffness, but despite higher carotid IMT, there was no increased carotid stiffness. They had higher aortic WI indices, but not WP. In contrast, in the carotid artery both WI and WP indices were greater. Aortic stiffness was related to forward carotid WP in the coarctation group, but not controls. These findings demonstrate that greater stiffness of the aorta leads to increased transmission of wave energy towards the brain. Non-invasive WI/WP analyses have the potential to be more widely deployed using the methods developed in this thesis, and may yield novel insights into the circulatory phenomena that are encountered in children and young people with congenital cardiac and vascular disease.
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ItemMinimising complications after surgical repair of coarctation of the aorta( 2018)Coarctation of the aorta is one of the most common congenital heart defects, often requiring surgery soon after birth. In Australia alone, approximately 150 babies are born with coarctation each year with an estimated 3,000 people living with a coarctation repair. Coarctation can no longer be considered a benign condition cured by surgery. There has been renewed interest into the late outcomes after coarctation repair as rates of late aortic arch reobstruction and late hypertension have recently been demonstrated to be much higher than initially expected. Alarmingly, studies have demonstrated that this late hypertension is directly linked to mortality at a young age. Unfortunately, late hypertension is often resistant to conventional antihypertensive medication and its exact mechanism is unknown. This thesis aimed to (i) determine the long-term outcomes after surgical repair of coarctation with a particular focus on determining the mechanisms leading to the development of late hypertension, (ii) examine the impact of an associated bicuspid aortic valve on patients with previous coarctation repair, and (iii) examine the complication of vocal cord paresis after aortic arch repair via sternotomy approach. A broad range of potential mechanisms for late hypertension including mechanical, arterial wall, neural, and genetic factors were all explored. In this thesis, I present our current understanding of the population, their outcomes and risk factors for early and late complications, and, finally, present initial data serving as a foundation for a prospective aortic arch anomaly biobank and hypothesis-generated research. Through a collaboration with the Royal Brompton Hospital, London, UK, this thesis has also resulted in the largest and longest cohort study in the world comprising 834 coarctation patients spanning seven decades of follow-up. Through this thesis, I have demonstrated that: (i) there is likely a high prevalence of late hypertension after coarctation repair, (ii) there is significant device-dependence of 24-hour blood pressure monitoring devices, making the identification of the hypertensive patient challenging, (iii) the risk of late mortality is three times higher than a healthy matched population, with the majority of deaths attributable to complications related to hypertension, (iv) there is four times increased risk of aortic valve and ascending aortic interventions in those with an associated bicuspid aortic valve, (v) the use of extensive aortic arch repair techniques may reduce long-term complications, and (vi) there is a high incidence of left vocal cord paresis after aortic arch repair via sternotomy approach. This journey began when I was an undergraduate medical student investigating the outcomes of patients with coarctation repaired at The Royal Children’s Hospital. This thesis has refined our understanding and management of complications after coarctation repair and will ultimately improve the long-term outcomes of many patients with coarctation of the aorta.