Diagnosis and Treatment of the Cardiovascular Consequences of Fabry Disease

Fabry Disease (FD) has been a diagnostic challenge since it was first recognised in 1898, with patients traditionally suffering from considerable delay before a diagnosis is made. Cardiac involvement is the current leading cause of death in FD. A combination of improved enzyme assays, availability of genetic profiling, together with more organised clinical services for rare diseases, has led to a rapid growth in the prevalence of FD. The earlier and more frequent diagnosis of asymptomatic individuals before development of the phenotype has focussed attention on early detection of organ involvement and closer monitoring of disease progression. The high cost of enzyme replacement therapy at a time of constraint within many health economies moreover, has challenged clinicians to target treatment effectively. This article provides an outline of FD for the general physician and summarises the aetiology and pathology of FD, the cardiovascular (CV) consequences thereof, modalities used in diagnosis, and then discusses current indications for treatment, including pharmacotherapy and device implantation

Increased cardiac involvement in Fabry disease using blood-corrected native T1 mapping

Fabry disease (FD) is a rare lysosomal storage disorder resulting in myocardial sphingolipid accumulation which is detectable by cardiovascular magnetic resonance as low native T1. However, myocardial T1 contains signal from intramyocardial blood which affects variability and consequently measurement precision and accuracy. Correction of myocardial T1 by blood T1 increases precision. We therefore deployed a multicenter study of FD patients (n = 218) and healthy controls (n = 117) to investigate if blood-correction of myocardial native T1 increases the number of FD patients with low T1, and thus reclassifies FD patients as having cardiac involvement. Cardiac involvement was defined as a native T1 value 2 standard deviations below site-specific means in healthy controls for both corrected and uncorrected measures. Overall low T1 was 135/218 (62%) uncorrected vs. 145/218 (67%) corrected (p = 0.02). With blood-correction, 13/83 previously normal patients were reclassified to low T1. This reclassification appears clinically relevant as 6/13 (46%) of reclassified had focal late gadolinium enhancement or left ventricular hypertrophy as signs of cardiac involvement. Blood-correction of myocardial native T1 increases the proportion of FD subjects with low myocardial T1, with blood-corrected results tracking other markers of cardiac involvement. Blood-correction may potentially offer earlier detection and therapy initiation, but merits further prospective studies

Specific of Myocardial Perfusion Scintigraphy Compared to Invasive Coronary Angiography

Purpose: The NICE guidance has placed non-invasive ischaemia testing as the primary role for assessing patients with moderate pre test probability for obstructive coronary artery disease. Functional tests like MPI, have led to a reduced role for invasive coronary angiography (ICA) in initial patient assessment. Aim of our audit was to assess the specificity of our nuclear service compared with ICA retrospectively. The standard was set at a false positive rate of no more than 73%.Methods: A search was conducted (between Aug2012-Feb2013). MPIs were reported by a radiologist and a cardiologist. A standard 17-segment model was used for MPI interpretation. Coronary angiograms were interpreted for the absence/presence of epicardial luminal narrowing >50% by referencing the clinical report on the patient electronic record. The cases which were positive enough to warrant recommendation for ICA the true positive and false positive rate was determined.Results: This cross –sectional study included 51 cases.33 had a stenosis in a major coronary artery of>50% giving a true positive rate of 65%. There were18 false positive studies (35%). 5 cases were regarded as having evidence of transient ischaemic dilatation (TID), all of which had a subsequent negative angiogram.3 studies had notable artefact due to patient body habitus, or inability to position the patient optimally. The percentage of myocardium defects was determined for each case at stress. The average percentage in the true positive studies was 17%, in the false positive studies it was7%, excluding those regarding as having TID.Conclusions: MPI studies deemed sufficiently abnormal to justify a coronary angiogram have a moderate likelihood of predicting a significant stenosis being present on ICA. False positive scans are frequent when only TID and significant artefacts are present. It is likely that CT calcium scoring with MPI will increase the specifity of this imaging. It will also allow CT coronary angiography to be used in cases where artefact is present and the calcified atheroma burden is low.The audit standard was not met. Suggested changes in practice. 1. Greater caution in recommending ICA for cases where the only evidence for ischaemia is transient ischaemic cardiomyopathy. 2. Increased use of CT to determine cases where significant reversible ischaemia is present in the context of none or low burden of coronary calcification.Clinical Relevance/Application: MPI assesses myocardial perfusion by using radiotracers injected under stress/rest conditions

A systematic approach to echocardiography in hypertrophic cardiomyopathy: a guideline protocol from the British Society of Echocardiography.

Hypertrophic cardiomyopathy (HCM) is a relatively common inherited cardiac condition with a prevalence of approximately one in 500. It results in otherwise unexplained hypertrophy of the myocardium and predisposes the patient to a variety of disease-related complications including sudden cardiac death. Echocardiography is of vital importance in the diagnosis, assessment and follow-up of patients with known or suspected HCM. The British Society of Echocardiography (BSE) has previously published a minimum dataset for transthoracic echocardiography, providing the core parameters necessary when performing a standard echocardiographic study. However, for patients with known or suspected HCM, additional views and measurements are necessary. These additional views allow more subtle abnormalities to be detected or may provide important information in order to identify patients with an adverse prognosis. The aim of this Guideline is to outline the additional images and measurements that should be obtained when performing a study on a patient with known or suspected HCM

A supersonic crowdion in mica: Ultradiscrete kinks with energy between 40^{40}K recoil and transmission sputtering

In this chapter we analyze in detail the behaviour and properties of the kinks found in an one dimensional model for the close packed rows of potassium ions in mica muscovite. The model includes realistic potentials obtained from the physics of the problem, ion bombardment experiments and molecular dynamics fitted to experiments. These kinks are supersonic and have an unique velocity and energy. They are ultradiscrete involving the translation of an interstitial ion, which is the reason they are called 'crowdions'. Their energy is below the most probable source of energy, the decay of the $^{40}$K isotope and above the energy needed to eject an atom from the mineral, a phenomenon that has been observed experimentallyComment: 28 pages, 15 figure

Effects of Space Charge, Dopants, and Strain Fields on Surfaces and Grain Boundaries in YBCO Compounds

Statistical thermodynamical and kinetically-limited models are applied to study the origin and evolution of space charges and band-bending effects at low angle [001] tilt grain boundaries in YBa$_2$Cu$_3$O$_7$ and the effects of Ca doping upon them. Atomistic simulations, using shell models of interatomic forces, are used to calculate the energetics of various relevant point defects. The intrinsic space charge profiles at ideal surfaces are calculated for two limits of oxygen contents, i.e. YBa$_2$Cu$_3$O$_6$ and YBa$_2$Cu$_3$O$_7$. At one limit, O$_6$, the system is an insulator, while at O$_7$, a metal. This is analogous to the intrinsic and doping cases of semiconductors. The site selections for doping calcium and creating holes are also investigated by calculating the heat of solution. In a continuum treatment, the volume of formation of doping calcium at Y-sites is computed. It is then applied to study the segregation of calcium ions to grain boundaries in the Y-123 compound. The influences of the segregation of calcium ions on space charge profiles are finally studied to provide one guide for understanding the improvement of transport properties by doping calcium at grain boundaries in Y-123 compound.Comment: 13 pages, 5 figure

Systematic review of the incidence and clinical risk predictors of atrial fibrillation and permanent pacemaker implantation for bradycardia in Fabry disease

INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by enzyme deficiency, leading to glycosphingolipid accumulation. Cardiac accumulation triggers local tissue injury, electrical instability and arrhythmia. Bradyarrhythmia and atrial fibrillation (AF) incidence are reported in up to 16% and 13%, respectively. OBJECTIVE: We conducted a systematic review evaluating AF burden and bradycardia requiring permanent pacemaker (PPM) implantation and report any predictive risk factors identified. METHODS: We conducted a literature search on studies in adults with FD published from inception to July 2019. Study outcomes included AF or bradycardia requiring therapy. Databases included Embase, Medline, PubMed, Web of Science, CINAHL and Cochrane. The Risk of Bias Agreement tool for Non-Randomised Studies (RoBANS) was utilised to assess bias across key areas. RESULTS: 11 studies were included, eight providing data on AF incidence or PPM implantation. Weighted estimate of event rates for AF were 12.2% and 10% for PPM. Age was associated with AF (OR 1.05–1.20 per 1-year increase in age) and a risk factor for PPM implantation (composite OR 1.03). Left ventricular hypertrophy (LVH) was associated with AF and PPM implantation. CONCLUSION: Evidence supporting AF and bradycardia requiring pacemaker implantation is limited to single-centre studies. Incidence is variable and choice of diagnostic modality plays a role in detection rate. Predictors for AF (age, LVH and atrial dilatation) and PPM (age, LVH and PR/QRS interval) were identified but strength of association was low. Incidence of AF and PPM implantation in FD are variably reported with arrhythmia burden likely much higher than previously thought

Impact of methodology and the use of allometric scaling on the echocardiographic assessment of the aortic root and arch: a study by the Research and Audit Sub-Committee of the British Society of Echocardiography.

The aim of the study is to establish the impact of 2D echocardiographic methods on absolute values for aortic root dimensions and to describe any allometric relationship to body size. We adopted a nationwide cross-sectional prospective multicentre design using images obtained from studies utilising control groups or where specific normality was being assessed. A total of 248 participants were enrolled with no history of cardiovascular disease, diabetes, hypertension or abnormal findings on echocardiography. Aortic root dimensions were measured at the annulus, the sinus of Valsalva, the sinotubular junction, the proximal ascending aorta and the aortic arch using the inner edge and leading edge methods in both diastole and systole by 2D echocardiography. All dimensions were scaled allometrically to body surface area (BSA), height and pulmonary artery diameter. For all parameters with the exception of the aortic annulus, dimensions were significantly larger in systole (P<0.05). All aortic root and arch measurements were significantly larger when measured using the leading edge method compared with the inner edge method (P<0.05). Allometric scaling provided a b exponent of BSA(0.6) in order to achieve size independence. Similarly, ratio scaling to height in subjects under the age of 40 years also produced size independence. In conclusion, the largest aortic dimensions occur in systole while using the leading edge method. Reproducibility of measurement, however, is better when assessing aortic dimensions in diastole. There is an allometric relationship to BSA and, therefore, allometric scaling in the order of BSA(0.6) provides a size-independent index that is not influenced by the age or gender