A randomised controlled trial evaluating arrhythmia burden, risk of sudden cardiac death and stroke in patients with Fabry disease:The role of implantable loop recorders (RaILRoAD) compared with current standard practice

Background: Fabry disease (FD) is a genetic disorder caused by a deficiency in the enzyme alpha-galactosidase A, leading to an accumulation of glycosphingolipids in tissues across the body. Cardiac disease is the leading cause of morbidity and mortality. Advanced disease, characterised by extensive left ventricular hypertrophy, ventricular dysfunction and fibrosis, is known to be associated with an increase in arrhythmia. Data identifying risk factors for arrhythmia are limited, and no Fabry-specific risk stratification tool is available to select those who may benefit from initiation of medical or device therapy (implantable cardiac defibrillators). Current monitoring strategies have a limited diagnostic yield, and implantable loop recorders (ILRs) have the potential to change treatment and clinical outcomes. Aim: The aim of this study is to determine whether ILRs can (1) improve arrhythmia detection in FD and (2) identify risk predictors of arrhythmia. Methods: A prospective, 5-year, open-label, international, multi-centre randomised controlled trial of a minimum of 164 participants with genetically or enzymatically confirmed FD (or both) who have evidence of cardiac disease will be recruited from five centres: Queen Elizabeth Hospital, Birmingham, UK; Salford Royal Hospital, Salford, UK; Royal Free Hospital, London, UK; Addenbrookes Hospital, Cambridge, UK; and Westmead Hospital, Sydney, Australia. Participants will be block-randomised (1:1) to two study arms for cardiac monitoring (i) control arm: standard of care with annual 24 h or 5-day Holter monitor or (ii) treatment arm: continuous cardiac monitoring with ILR implantation plus standard of care. Participants will undergo multiple investigations - blood/urine biomarkers, 12-lead and advanced electrocardiogram (ECG) recording, echocardiography and cardiovascular magnetic resonance (CMR) imaging - at baseline and 6-12 monthly follow-up visits. The primary endpoint is identification of arrhythmia requiring initiation or alteration in therapy. Secondary outcome measures include characterising the risk factors associated with arrhythmia and outcome data in the form of imaging, ECG and blood biomarkers. Discussion: This is the first study evaluating arrhythmia burden and the use of ILR across the spectrum of risk profiles in Fabry cardiomyopathy. This will enable detailed characterisation of arrhythmic risk predictors in FD and ultimately support formulation of Fabry-specific guidance in this high-risk population. Trial registration: ClinicalTrials.gov (NCT03305250). Registered on 9 October 2017

Study of indications for cardiac device implantation and utilisation in Fabry cardiomyopathy

Background: Fabry disease is a treatable X-linked condition leading to progressive cardiomyopathy, arrhythmia and premature death. Atrial and ventricular arrhythmias contribute significantly to adverse prognosis; however, guidance to determine which patients require cardiovascular implantable electronic devices (CIEDs) is sparse. We aimed to evaluate indications for implantation practice in the UK and quantify device utilisation. Methods: In this retrospective study, we included demographic, clinical and imaging data from patients in four of the largest UK Fabry centres. Ninety patients with Fabry disease were identified with CIEDs implanted between June 2001 and February 2018 (FD-CIED group). To investigate differences in clinical and imaging markers between those with and without devices, these patients were compared with 276 patients without a CIED (FD-control). Results: In the FD-CIED group, 92% of patients with permanent pacemakers but only 28% with implantable cardioverter-defibrillators had a class 1 indication for implantation. A further 44% of patients had defibrillators inserted for primary prevention outside of current guidance. The burden of arrhythmia requiring treatment in the FD-CIED group was high (asymptomatic atrial fibrillation: 29%; non-sustained ventricular tachycardia requiring medical therapy alone: 26%; sustained ventricular tachycardia needing anti-tachycardia pacing/defibrillation: 28%). Those with devices were older, had greater LV mass, more scar tissue and larger atrial size. Conclusions: Arrhythmias are common in Fabry patients. Those with cardiac devices had high rates of atrial fibrillation requiring anticoagulation and ventricular arrhythmia needing device treatment. These are as high as those in hypertrophic cardiomyopathy, supporting the need for Fabry-specific indications for device implantation

Sex dimorphism in the myocardial response to aortic stenosis

Objectives: The goal of this study was to explore sex differences in myocardial remodeling in aortic stenosis (AS) by using echocardiography, cardiac magnetic resonance (CMR), and biomarkers. Background: AS is a disease of both valve and left ventricle (LV). Sex differences in LV remodeling are reported in AS and may play a role in disease phenotyping. Methods: This study was a prospective assessment of patients awaiting surgical valve replacement for severe AS using echocardiography, the 6-min walking test, biomarkers (high-sensitivity troponin T and N-terminal pro-brain natriuretic peptide), and CMR with late gadolinium enhancement and extracellular volume fraction, which dichotomizes the myocardium into matrix and cell volumes. LV remodeling was categorized into normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy

Precision measurement of cardiac structure and function in cardiovascular magnetic resonance using machine learning

BACKGROUND: Measurement of cardiac structure and function from images (e.g. volumes, mass and derived parameters such as left ventricular (LV) ejection fraction [LVEF]) guides care for millions. This is best assessed using cardiovascular magnetic resonance (CMR), but image analysis is currently performed by individual clinicians, which introduces error. We sought to develop a machine learning algorithm for volumetric analysis of CMR images with demonstrably better precision than human analysis. METHODS: A fully automated machine learning algorithm was trained on 1923 scans (10 scanner models, 13 institutions, 9 clinical conditions, 60,000 contours) and used to segment the LV blood volume and myocardium. Performance was quantified by measuring precision on an independent multi-site validation dataset with multiple pathologies with n = 109 patients, scanned twice. This dataset was augmented with a further 1277 patients scanned as part of routine clinical care to allow qualitative assessment of generalization ability by identifying mis-segmentations. Machine learning algorithm ('machine') performance was compared to three clinicians ('human') and a commercial tool (cvi42, Circle Cardiovascular Imaging). FINDINGS: Machine analysis was quicker (20 s per patient) than human (13 min). Overall machine mis-segmentation rate was 1 in 479 images for the combined dataset, occurring mostly in rare pathologies not encountered in training. Without correcting these mis-segmentations, machine analysis had superior precision to three clinicians (e.g. scan-rescan coefficients of variation of human vs machine: LVEF 6.0% vs 4.2%, LV mass 4.8% vs. 3.6%; both P < 0.05), translating to a 46% reduction in required trial sample size using an LVEF endpoint. CONCLUSION: We present a fully automated algorithm for measuring LV structure and global systolic function that betters human performance for speed and precision

Evolving applications of cardiovascular magnetic resonance in clinical cardiology

ABSTRACT Cardiovascular magnetic resonance (CMR) is a non-invasive imaging technique with increasing use and demand worldwide both in the clinical and research arenas. Its strength is accurate quantification of cardiac structure and function, and unique abilities with tissue characterisation. The most common indications for CMR in general include the assessment of ischaemia and viability, and cardiomyopathy. This thesis explores the application of CMR in the assessment of cardiovascular disease in two distinct but uncommon populations encompassed in these categories – chronic social cocaine users and patients with Fabry disease, chosen because of the unique diagnostic challenges related to each, and persistent difficulties risk stratifying and targeting treatment in these settings. Chapter 1 provides an introduction with a literature review of the common and important clinical and research applications of CMR, as well as a detailed review of the cardiovascular effects of cocaine use and Fabry disease. It also states the overarching hypotheses and aim of this thesis. Chapter 2 outlines the general CMR methodologies utilised in the studies encompassed in this thesis. Chapter 3 reports the harmful cardiovascular effects of chronic social cocaine use in otherwise healthy young individual with the aid of CMR, including increases in systolic blood pressure, myocardial mass, and aortic stiffness, but no evidence of previous silent myocardial infarctions. Given precise measurements of left ventricular mass (LVM) are important both clinically and from a research perspective, Chapter 4 addresses the methods of quantifying myocardial mass in hypertrophied hearts by either including or excluding the left ventricular papillary muscles (LVPM) in the total mass. This pilot study includes male patients with Fabry disease and left ventricular hypertrophy (LVH) and shows that the LVPM are critical to total LVM quantification. To follow on from this, Chapter 5 explores the same concept but applied to a diverse range of patient cohorts with LVH. It shows that there is disproportionate hypertrophy of the LVPMs in Fabry disease with and without LVH. It also provides further insight into the disease biology in Fabry disease by characterising the papillary muscles with T1 mapping. Chapter 6 explores the utility of CMR in identifying cardiac involvement in patients with Fabry disease, and how it can potentially affect management by reclassifying patients and allowing consideration of targeted therapy. Finally, Chapter 7 uses a combination of CMR parametric mapping techniques and serum biomarkers to show that cardiac involvement of Fabry disease with late gadolinium enhancement is a chronic inflammatory cardiomyopathy. These findings offer potential for therapeutic targets and management guidance

Cardiovascular magnetic resonance of a hiatus hernia causing positional cardiac compression

A69-year-old lady with intermittent breathlessness and chest pain underwent cardiovascular magnetic resonance (CMR) in the supine position. A large hiatus herniawas seen compressing the left ventricle, atrium, and mitral annulus. The CMR, including adenosine stress perfusion, was otherwise normal. The patient was immediately repositioned into the prone position and rescanned. In this position, the cardiac compression from the hiatus hernia was reduced, thus demonstrating its positional nature. Positional cardiac compression may in fact be an under-diagnosed phenomenon. Echocardiography in the left lateral decubitus position may not detect compression that occurs only when supine, unless an index of suspicion calls to reposition the patient, which is feasible with echocardiography. CMR may be more likely to detect this rare phenomenon given its supine nature