Brain Volumetrics, Regional Cortical Thickness and Radiographic Findings in Adults with Cyanotic Congenital Heart Disease

AbstractBackgroundChronic cyanosis in adults with congenital heart disease (CHD) may cause structural brain changes that could contribute to impaired neurological functioning. The extent of these changes has not been adequately characterized.HypothesisWe hypothesized that adults with cyanotic CHD would have widespread changes including abnormal brain volumetric measures, decreased cortical thickness and an increased burden of small and large vessel ischemic changes.MethodsTen adults with chronic cyanosis from CHD (40±4years) and mean oxygen saturations of 82±2% were investigated using quantitative MRI. Hematological and biochemical parameters were also assessed. All subjects were free from major physical or intellectual impairment. Brain volumetric results were compared with randomly selected age- and sex-matched controls from our database of normal subjects.ResultsFive of 10 cyanotic subjects had cortical lacunar infarcts. The white matter (WM) hyperintensity burden was also abnormally high (Scheltens Scale was 8±2). Quantitative MRI revealed evidence of extensive generalized WM and gray matter (GM) volumetric loss; global GM volume was reduced in cyanosed subjects (630±16 vs. 696±14mL in controls, p=0.01) as was global WM volume (471±10 vs. 564±18mL, p=0.003). Ventricular cerebrospinal fluid volume was increased (35±10 vs. 26±5mL, p=0.002). There were widespread regions of local cortical thickness reduction observed across the brain. These changes included bilateral thickness reductions in the frontal lobe including the dorsolateral prefrontal cortex and precentral gyrus, the posterior parietal lobe and the middle temporal gyrus. Sub-cortical volume changes were observed in the caudate, putamen and in the thalamus (p≤0.005 for all regions). Cortical GM volume negatively correlated with brain natriuretic peptide (R=−0.89, p=0.009), high sensitivity C-reactive protein (R=−0.964, p<0.0001) and asymmetric dimethylarginine (R=−0.75, p=0.026) but not with oxygen saturations, packed cell volume or viscosity.ConclusionsWe present the first comprehensive analysis of brain structure in adults with chronic neurocyanosis due to congenital heart disease. We demonstrate clear evidence for marked macro- and microvascular injury. Cyanotic patients show global evidence for reduced brain volume as well as specific foci of cortical thickness reduction. The GM volume loss correlated with hsCRP, BNP and ADMA suggesting that inflammation, neurohormonal activation and endothelial dysfunction may have important roles in its pathogenesis

Hepatic and renal end-organ damage in the Fontan circulation: a report from the Australian and New Zealand Fontan Registry

Background: Hepatic and renal dysfunction have been observed in survivors of the Fontan procedure, however their incidence and associated factors remain poorly defined. Methods: A total of 152 participants from a Registry of 1528 patients underwent abdominal ultrasound, transient elastography (FibroScan), serum fibrosis score (FibroTest), in vivo Tc-99m DTPA measurement of glomerular filtration rate (mGFR), and urine albumin-creatinine ratio (ACR). Results: Mean age and time since Fontan were 19.8 ± 9.3 and 14.1 ± 7.6 years, respectively. Features suggestive of hepatic fibrosis were observed on ultrasound in 87/143 (61%) and no patient was diagnosed with hepatocellular carcinoma. FibroScan median kPa was ≥10 in 117/133 (88%), ≥15 in 75/133 (56%), and ≥20 in 41/133 (31%). Fifty-four patients (54/118, 46%) had a FibroTest score ≥0.49 (equivalent to ≥F2 fibrosis). FibroTest score correlated with FibroScan value (r = 0.24, p = 0.015) and ACR (r = 0.29, p = 0.002), and patients with ultrasound features of hepatic fibrosis had a higher FibroScan median kPa (19.5 vs 15.4, p = 0.002). Renal impairment was mild (mGFR 60–89 ml/min/1.73 m) in 46/131 (35%) and moderate (mGFR 30–59 ml/min/1.73 m) in 3/131 (2%). Microalbuminuria was detected in 52/139 participants (37%). By multivariable analysis, time since Fontan was associated with increased FibroScan median kPa (β = 0.89, 95% CI 0.54–1.25, p = 0.002) and decreased mGFR (β = −0.77, 95% CI −1.29–0.24, p = 0.005). Conclusions: In the second decade after Fontan hepatic and renal structure and function are abnormal in a significant number of patients: close to 60% have ultrasonographic evidence of structural hepatic abnormalities, 46% have elevated serum hepatic fibrosis scores, and 57% have either reduced glomerular filtration rate or microalbuminuria. Hepatic and renal function should be monitored for potential impacts on outcomes after Fontan completion

Pathophysiological Abnormalities in Adults with Complex Congenital Heart Disease

This thesis examines the pathophysiology that underlies several important, yet poorly characterised, issues that affect adults with congenital heart disease (CHD). Cardiac arrhythmia is the most common cause for hospitalisation in this group; altered systemic venous anatomy occurs frequently in subjects with CHD however the implications for electrophysiological procedures had not been clearly described in the literature. In Chapter 3 we demonstrate that systemic venous anomalies frequently complicate electrophysiologic testing and catheter ablation. In Chapter 4 we describe atrioventricular nodal re-entrant tachycardia in the setting of atrioventricular septal defect. We found that the atrioventricular conduction tissue is displaced inferoposteriorly in patients with atrioventicular septal defect and is located between the coronary sinus orifice and the nearest part of the atrioventricular valve. Subjects with cyanotic CHD have the worst functional status and mortality rates of the adult CHD group; vascular events such as stroke and pulmonary thromboemboli are important contributors to clinical deterioration and/or death. Endothelial dysfunction has an important role in the development of vascular disease in other conditions but data investigating such pathophysiology in the setting of cyanotic CHD was virtually non-existent until now; in Chapter 5 we investigate endothelial function in the brachial artery, distal arterioles of the finger and retinal vascular bed as well as circulating endothelial progenitor cells in adults with cyanotic CHD. We found that a widespread endotheliopathy exists in adults with cyanotic CHD and reduced numbers of circulating endothelial cells potentially underlie these observations. Data were also lacking that describe the neuro-ophthalmological consequences of chronic cyanosis in CHD that may have important implications for intellectual and physical functioning; we address this issue in Chapter 6 by undertaking detailed ophthalmic investigation including visual field testing and optical coherence tomography of the optic nerve head together with cerebral MRI and brain volumetrics. White matter small vessel ischaemic change and lacunar infarction were frequently observed associated with reduced white matter loss and regional grey matter loss. This occurred in association with retinal nerve fibre layer thinning at the optic nerve head and reduced visual field sensitivity. The retinal vascular bed exhibits increased vascular branching, calibre, tortuosity and fractal dimension reflecting a degree of vascular remodelling in the setting of chronic cyanosis. The Fontan procedure is now the surgical option of choice in suitable candidates born with essentially single-ventricle CHD. In Chapter 7, we investigate the complex interplay of factors that contribute to exercise incapacity in this group and describe, for the first time, a coexistent sarcopenia in the Fontan population that may have important consequences for cardiac and physical functioning. In Chapter 8 we investigate the effects of an intensive, 20-week, total body resistance training program in these subjects. Post-training, subjects had improved muscle strength and muscle mass, peak exercise capacity, muscle aerobic function as well as augmented cardiac function and reduced respiratory dependence. Taken together, these studies contribute to an understanding of the pathophysiology of disease in young adult survivors with the most complex forms of CHD, pointing the way towards a hopefully brighter future of therapeutic options

O2 pulse slope correlates with stroke volume during exercise in patients with a Fontan circulation

Background Peak oxygen pulse (O2pulse=oxygen consumption/heart rate) is calculated by the product of stroke volume (SV) and oxygen extraction. It has been shown to be reduced in patients with a Fontan circulation. However, in the Fontan population, it may be a poor marker of SV. We propose that the slope of the O2 pulse curve may be more reflective of SV during exercise.Methods We analysed cardiopulmonary exercise test data in 22 subjects with a Fontan circulation (cohort A) and examined the association between peak SV during exercise (aortic flow measured on exercise cardiac MRI), and O2 pulse parameters (absolute O2 pulse and O2 pulse slopes up to anaerobic threshold (AT) and peak exercise). In a separate Fontan cohort (cohort B, n=131), associations between clinical characteristics and O2 pulse kinetics were examined.Results In cohort A, peak aortic flow was moderately and significantly associated with O2pulseslopePEAK (r=0.47, p=0.02). However, neither absolute O2pulseAT nor O2pulsePEAK was significantly associated with peak aortic flow. In cohort B, O2pulseslopePEAK and O2pulseslopeAT were not significantly associated with clinical parameters, apart from a weak association with forced vital capacity.Conclusion The slope of the O2 pulse curve to peak exercise may be more reflective of peak SV in the Fontan population than a single peak O2 pulse value

Ophthalmological consequences of cyanotic congenital heart disease : vascular parameters and nerve fibre layer

Background: This study investigated the long-term ophthalmological consequences of cyanotic congenital heart disease (CHD). Design: Cross-sectional study, tertiary referral setting. Participants: Thirteen adults with cyanotic CHD (40 ± 4 years). Age- and sex-matched healthy controls underwent aspects of the protocol. Methods: Cyanosed subjects had a full ophthalmic examination, visual fields, scanning laser ophthalmoscopy and optical coherence tomography to assess retinal nerve fibre layer (RNFL), retinal photography and cerebral magnetic resonance imaging (MRI). Main Outcome Measures: RNFL thickness and quantitative analysis of retinal vessels with fractal dimension, branching and central retinal arterial equivalent (CRAE) and central retinal venous equivalent (CRVE). Results: No abnormalities of anatomy, motility, intraocular pressure or anterior segments were detected apart from one subject who had bilateral cataracts. Corrected visual acuity was normal in all but one cyanosed subject. Clinical examination revealed dilated retinal vasculature in 12/13 cyanosed subjects and increased tortuosity in 8/13. In the setting of cyanosis, skeletonized retinal arterial and venous beds had higher fractal dimension and increased branching (P ≤ 0.01, n = 11 for all); retinal vessels were dilated (CRAE: 227 vs. 183, n = 11, P < 0.0001; CRVE: 254 vs. 221, n = 11, P = 0.01). Visual fields showed scotomas in two subjects associated with RNFL thinning. No disc oedema was detected. 6/13 subjects' RNFL thickness fell below the normal 95% confidence interval in at least one sector without explanatory cerebral pathology (P < 0.0001, n = 13). Mean RNFL thickness correlated with MRI cerebral white matter volume (R = 0.67, P = 0.035). Conclusions: Cyanosed subjects had vessel dilatation, increased branching and tortuosity. RNFL and visual field thresholds were reduced suggesting impaired neuro-ophthalmological functioning.9 page(s

Platypnea‐Orthodeoxia Syndrome in the Setting of Patent Foramen Ovale Without Pulmonary Hypertension or Major Lung Disease

Background Patent foramen ovale (PFO)‐associated platypnea‐orthodeoxia syndrome is characterized by dyspnea and hypoxemia when upright. The pathogenesis is thought to involve an increase in right atrial pressure or change in degree of right to left shunting with upright posture. Methods and Results We sought to characterize patients with platypnea‐orthodeoxia syndrome related to PFO without pulmonary hypertension. We retrospectively reviewed databases at 3 tertiary referral hospitals in New South Wales, Australia from 2000 to 2019. Fourteen patients with a mean age of 69±14 years had a PFO with wide tunnel separation. Mean New York Heart Association Classification was II (±0.9) and 7 inpatients had been confined to bed (from postural symptoms). Baseline oxygen saturations supine were 93%±5% and 84%±6% upright. Two patients had a minor congenital heart defect and 4 had mild parenchymal lung disease with preserved lung function. The mean aortic root diameter was 37±6 mm and distance between aortic root and posterior atrial wall was 16±2 mm. Platypnea‐orthodeoxia syndrome was preceded by surgery in 5 patients and 1 patient had mild pneumonia. Successful closure of the PFO using an Amplatzer device was performed in 11 of 14 patients. Post‐closure, all patients had New York Heart Association Classification I (improvement 1.6±0.9, P<0.003) and semi‐recumbent oxygen saturations increased by 13%±8% (P<0.001, n=10). Conclusions Platypnea‐orthodeoxia syndrome is a debilitating condition, curable by PFO closure. Anatomical distortion of the atrial septum related to a dilated aortic root or shortening of the distance between the aortic root and posterior atrial wall may contribute to the syndrome

Algorithmic complexity stratification for congenital heart disease patients

Background: Congenital Heart Disease (CHD) encompasses a huge variety of rare diagnoses that range in complexity and comorbidity. To help build clinical guidelines, plan health services and conduct statistically powerful research on such a disparate set of diseases there have been various attempts to group pathologies into mild, moderate, or severe disease. So far, however, these complexity scores have required manual specialist input for every case, and are therefore missing in large databases where this is impractical, or quickly outdated when guidelines are revised. Methods: We used the up-to-date European Society of Cardiology guidelines to create an algorithm to assign complexity scores to CHD patients using only their diagnosis list. Two CHD specialists then independently assigned complexity scores to a random sample of patients. Results: Our algorithm was 96% accurate where both specialists agreed on a complexity score; this occurred 68% of the time overall, and 79% of the time in moderate or complex CHD. The algorithm “failed” mainly when diagnoses were insufficiently specific, usually for septal defects (where size was unspecified), or where complexity depends on the procedure performed (e.g. atrial/arterial switch for transposition of the great arteries). Conclusions: We were able to algorithmically determine the complexity scores of a majority of patients with CHD based on their diagnosis list alone. This could allow for automatic complexity scoring of most patients in large CHD databases, for example our own Registry of the Congenital Heart Alliance of Australia and New Zealand. This will facilitate targeted research into the management, outcomes and burden of CHD