Shanat Baig

Cardiac Phenotype of Prehypertrophic Fabry Disease

Background: Fabry disease (FD) is a rare and treatable X-linked lysosomal storage disorder. Cardiac involvement determines outcomes; therefore, detecting early changes is important. Native T1 by cardiovascular magnetic resonance is low, reflecting sphingolipid storage. Early phenotype development is familiar in hypertrophic cardiomyopathy but unexplored in FD. We explored the prehypertrophic cardiac phenotype of FD and the role of storage. Methods and Results: A prospective, international multicenter observational study of 100 left ventricular hypertrophy–negative FD patients (mean age: 39±15 years; 19% male) and 35 age- and sex-matched healthy volunteers (mean age: 40±14 years; 25% male) who underwent cardiovascular magnetic resonance, including native T1 and late gadolinium enhancement, and 12-lead ECG. In FD, 41% had a low native T1 using a single septal region of interest, but this increased to 59% using a second slice because early native T1 lowering was patchy. ECG abnormalities were present in 41% and twice as common with low native T1 (53% versus 24%; P=0.005). When native T1 was low, left ventricular maximum wall thickness, indexed mass, and ejection fraction were higher (maximum wall thickness 9±1.5 versus 8±1.4 mm, P<0.005; indexed left ventricular mass 63±10 versus 58±9 g/m2, P<0.05; and left ventricular ejection fraction 73±8% versus 69±7%, P<0.01). Late gadolinium enhancement was more likely when native T1 was low (27% versus 6%; P=0.01). FD had higher maximal apical fractal dimensions compared with healthy volunteers (1.27±0.06 versus 1.24±0.04; P<0.005) and longer anterior mitral valve leaflets (23±2 mm versus 21±3 mm; P<0.005). Conclusions: There is a detectable prehypertrophic phenotype in FD consisting of storage (low native T1), structural, functional, and ECG changes.

Insight into hypertrophied hearts: a cardiovascular magnetic resonance study of papillary muscle mass and T1 mapping.

Aims Left ventricular papillary muscles (LVPM) can appear disproportionately hypertrophied, particularly in Fabry disease (FD) where storage appears detectable by cardiovascular magnetic resonance (CMR) T1 mapping. The aim of the study was to measure LVPM mass in heart diseases with left ventricular hypertrophy (LVH) and to gain insight into the mechanisms of LVPM hypertrophy in FD. Methods and results Four hundred and seventy-eight cases were retrospectively recruited: 125 FD, 85 hypertrophic cardiomyopathy (HCM), 67 amyloid, 82 aortic stenosis (AS), 40 hypertension, 79 controls. LVPM contribution to LVM was manually contoured on CMR short axis cines. T1 values (septal, LVPM) were measured using ShMOLLI sequences in FD and controls. LVPM contribution to LVM was highest in LVH+ve FD and significantly increased compared to all other LVH+ve groups (FD 13 ± 3%, HCM 10 ± 3%, amyloid 8 ± 2%, AS 7 ± 3%, hypertension 7 ± 2%, controls 7 ± 1%; P < 0.001). LVH+ve HCM also had significantly increased LVPM. In LVH-ve cohorts, only FD had significantly increased LVPM (11 ± 3%; P < 0.001). In FD there was concordant septal and LVPM T1. LVH+ve FD: when septal T1 was low, LVPM T1 was low in 90%. LVH-ve FD: when septal T1 was normal, LVPM T1 was normal in 70% (indicating no detectable storage); when septal T1 was low, 75% had low LVPM T1 (indicating storage). LVPM hypertrophy was similar between the low and normal septal T1 groups (11 ± 3% vs. 10 ± 3%, P = 0.08). Conclusion Disproportionate hypertrophy of LVPMs in LVH+ve hearts occurred in FD and HCM. This phenomenon also occurred in LVH-ve FD. Low T1 was not always present in FD LVPM hypertrophy, implying additional mechanisms activating hypertrophy signalling pathways.

Ventricular arrhythmia and sudden cardiac death in Fabry disease: a systematic review of risk factors in clinical practice

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of α-galactosidase A enzyme. Cardiovascular (CV) disease is a common cause of mortality in FD, in particular as a result of heart failure and arrhythmia, with a significant proportion of events categorized as sudden. There are no clear models for risk prediction in FD. This systematic review aims to identify the risk factors for ventricular arrhythmia (VA) and sudden cardiac deaths (SCD) in FD. A systematic search was performed following PRISMA guidelines of EMBASE, Medline, PubMed, Web of Science, and Cochrane from inception to August 2016, focusing on identification of risk factors for the development of VA or SCD. Thirteen studies were included in the review (n = 4185 patients) from 1189 articles, with follow-up of 1.2-10 years. Weighted average age was 37.6 years, and 50% were male. Death from any cause was reported in 8.3%. Of these, 75% was due to CV problems, with the majority being SCD events (62% of reported deaths). Ventricular tachycardia was reported in 7 studies, with an average prevalence of 15.3%. Risk factors associated with SCD events were age, male gender, left ventricular hypertrophy, late gadolinium enhancement on CV magnetic resonance imaging, and non-sustained ventricular tachycardia. Although a multi-system disease, FD is a predominantly cardiac disease from a mortality perspective, with death mainly from SCD events. Limited evidence highlights the importance of clinical and imaging risk factors that could contribute to improved decision-making in the management of FD.

Global longitudinal strain, myocardial storage and hypertrophy in Fabry disease

Introduction Detecting early cardiac involvement in Fabry disease (FD) is important because therapy may alter disease progression. Cardiovascular magnetic resonance (CMR) can detect T1 lowering, representing myocardial sphingolipid storage. In many diseases, early mechanical dysfunction may be detected by abnormal global longitudinal strain (GLS). We explored the relationship of early mechanical dysfunction and sphingolipid deposition in FD. Methods An observational study of 221 FD and 77 healthy volunteers (HVs) who underwent CMR (LV volumes, mass, native T1, GLS, late gadolinium enhancement), ECG and blood biomarkers, as part of the prospective multicentre Fabry400 study. Results All FD had normal LV ejection fraction (EF 73%±8%). Mean indexed LV mass (LVMi) was 89±39 g/m2 in FD and 55.6±10 g/m2 in HV. 102 (46%) FD participants had left ventricular hypertrophy (LVH). There was a negative correlation between GLS and native T1 in FD patients (r=−0.515, p<0.001). In FD patients without LVH (early disease), as native T1 reduced there was impairment in GLS (r=−0.285, p<0.002). In the total FD cohort, ECG abnormalities were associated with a significant impairment in GLS compared with those without ECG abnormalities (abnormal: −16.7±3.5 vs normal: −20.2±2.4, p<0.001). Conclusions GLS in FD correlates with an increase in LVMi, storage and the presence of ECG abnormalities. In LVH-negative FD (early disease), impairment in GLS is associated with a reduction in native T1, suggesting that mechanical dysfunction occurs before evidence of sphingolipid deposition (low T1). Trial registration number NCT03199001; Results.

Reference ranges for three-dimensional feature tracking cardiac magnetic resonance: comparison with two-dimensional methodology and relevance of age and gender

Myocardial deformation is a sensitive marker of sub-clinical myocardial dysfunction that carries independent prognostic significance across a broad range of cardiovascular diseases. It is now possible to perform 3D feature tracking of SSFP cines on cardiac magnetic resonance imaging (FT-CMR). This study provides reference ranges for 3D FT-CMR and assesses its reproducibility compared to 2D FT-CMR. One hundred healthy individuals with 10 men and women in each of 5 age deciles from 20 to 70 years, underwent 2D and 3D FT-CMR of left ventricular myocardial strain and strain rate using SSFP cines. Good health was defined by the absence of hypertension, diabetes, obesity, dyslipidaemia, or any cardiovascular, renal, hepatic, haematological and systemic inflammatory disease. Normal values for myocardial strain assessed by 3D FT-CMR were consistently lower compared with 2D FT-CMR measures [global circumferential strain (GCS) 3D − 17.6 ± 2.6% vs. 2D − 20.9 ± 3.7%, P < 0.005]. Validity of 3D FT-CMR was confirmed against other markers of systolic function. The 3D algorithm improved reproducibility compared to 2D, with GCS having the best inter-observer agreement [intra-class correlation (ICC) 0.88], followed by global radial strain (GRS; ICC 0.79) and global longitudinal strain (GLS, ICC 0.74). On linear regression analyses, increasing age was weakly associated with increased GCS (R2 = 0.15, R = 0.38), peak systolic strain rate, peak late diastolic strain rate, and lower peak early systolic strain rate. 3D FT-CMR offers superior reproducibility compared to 2D FT-CMR, with circumferential strain and strain rates offering excellent intra- and inter-observer variability. Normal range values for myocardial strain measurements using 3D FT-CMR are provided.

49 Predicting risk of scd in fabry disease: a single centre experience

Introduction Fabry disease (FD) is a rare X-linked lysosomal storage disorder with a variable cardiac phenotype and a defined risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD). To-date however, there is no accepted tool for risk prediction in FD and the ESC calculator in hypertrophic cardiomyopathy specifically excludes lysosomal storage diseases. Data on the prevalence of VA and SCD are restricted to single centre studies and registry data. These have identified individual risk factors including age, QRS duration>120 ms, left atrial dilatation (LA), late gadolinium enhancement on cardiac magnetic resonance (CMR) imaging (LGE), and left ventricular hypertrophy (LVH). The aim of this study was to assess the prevalence of these risk factors in a Regional FD centre and to examine known markers associated with increased cardiac mortality in FD to comprehensively assess risk. Methods This was a retrospective cross sectional observational study of patients with a proven diagnosis of FD (genetic and clinical markers) attending the Regional Centre for Rare Diseases in Birmingham between 2012–16. As part of routine annual assessment, patients underwent 12-lead ECG, 24 hour holter monitoring, transthoracic echocardiography and multi-parametric CMR. The cohort was divided into 2 groups: 1) a high risk group defined by presence of either VA (≥3 consecutive ventricular beats at a rate ≥120 beats per minute) or SCD; 2) all other patients. In addition to the above 5 risk factors, genotype (cardiac variant v non-cardiac variant), high sensitivity troponin (HS Tn) and NT pro-B natriuretic peptide were included. The frequency and significance of each of these proposed risk factors was studied. Fisher’s exact test was used to perform statistical analysis. Results In total 57 patients (male gender 42%, age mean 47±18 years.) were studied, of whom 13 patients had a documented VA and 2 patients suffered SCD. 11/13 in high risk group were on ERT (7±6 years.) and 21/44 in the remainder (6±3.8 years.). Identified risk factors and prevalence are outlined in Table 1. Male gender, age>50, LVH, LGE, QRS>120 ms were all more frequent in those with VA or SCD but risk was also associated with increased HS Tn and NT pro-BNP. The presence of a cardiac variant genotype did not appear to influence risk. Outcome These data confirm specific demographic, electrical and structural risk factors for VA and SCD in FD, although these are also present in those without arrhythmic events. Large multi-centre prospective studies are needed to further define the relative importance of these risk factors and their potential inter-relationship. Abstract 49 Table 1 Risk Predictors Patients with VA or SCD Patients without VA/SCD P value Male gender 9/13 (69%) 15/44 (34%) 0.05 Age>50 years 11/13 (85%) 20/44 (45%) 0.02 Left ventricular hypertrophy 13/13 (100%) 19/44 (43%) 0.0002 Presence of LGE 7/10 (70%) 12/38 (32%) 0.03 QRS duration>120 ms 7/13 (54%) 12/38 (32%) 0.03 Dilated left atrium 6/13 (46%) 9/44 (20%) 0.08 Stage ≥3 CKD 4/13 (31%) 11/44 (25%) 0.72 Classical variant 10/13 (77%) 30/44 (68%) 0.73 Positive HS troponin (>25 ng/L) 8/8 (100%) 16/33 (48%) 0.01 BNP >400 (ng/L) 10/13 (77%) 14/42 (33%) 0.009

11 Cpex testing detects subclinical cardiac limitation to exercise in early stage ckd

Introduction Effort tolerance is impaired in end stage kidney disease. Peak oxygen uptake (VO2peak) has been shown to be a powerful predictor of survival in haemodialysis patients. A low VO2peak and percent predicted VO2 at the anaerobic threshold (VO2 AT) have also been associated with excess mortality in patients undergoing kidney transplantation. Data on effort tolerance and cardiovascular disease in early chronic kidney disease (CKD) are very sparse though it is well recognised that cardiovascular mortality begins to increase at a glomerular filtration rate (eGFR) of about 75ml/min/m2. Methods This study examined effort tolerance, cardiac structure and function in 60 patients with CKD (stages 2 to 5) without known cardiovascular disease or diabetes. All patients underwent a cardiopulmonary exercise bicycle test using an individualised ramp protocol. Myocardial ischaemia was excluded by exercise stress echocardiography or 99m technetium tetrofosmin single photon electron computed tomography. Lung disease was excluded by formal lung function testing. Cardiac magnetic resonance imaging without gadolinium contrast was used to assess cardiac function and structure. The Kruskall Wallis test was used to compare the difference in mean values across stages of CKD. Correlation coefficients were measured to look for trends between continuous variables. Results Table 1 shows the baseline characteristics per CKD stage. Percent predicted peak VO2 was negatively associated with eGFR (r=−0.358, p=0.007) even after correction for age and haemoglobin (p=0.005). NT pro-BNP was negatively associated with eGFR (r=−0.586, p=0.001), even after similar correction (p<0.001). The percent predicted VO2 at the anaerobic threshold was also negatively associated with worsening eGFR (r=0.282, p=0.039). Exercise capacity (VO2 AT) was negatively associated with increasing LV mass (r=−0.382, p=0.006) but there was no significant association with left ventricular (LV) size, ejection fraction or global longitudinal strain. Discussion and implications Effort tolerance falls from the earliest stages of CKD in association with a progressive increase in LV mass and NT pro-BNP. This is the first study to examine exercise capacity in patients with early stage CKD in whom coronary artery disease has been excluded, and further study is needed to confirm whether the reduction in exercise capacity is a reflection of diastolic impairment and myocardial fibrosis that characterise end-stage kidney disease.Abstract 11 Table 1 Baseline demographics across each stage of CKD CKD stage?2 n=14 CKD Stage?3 n=17 CKD Stage?4 n=9 CKD Stage?5 n=21 P Value Age (years) 59 (45–67) 65 (54–67) 57 (53–69) 46 (33–58) 0.14 Male 8 (57%) 10 (59%) 6 (67%) 11 (55%) 0.912 Hg (g/L) 134±38 135±11 130±15 107±47 0.003 NT-pro BNP 68±70 156±152 189±115 631±651 0.001 EF (%) 71±7 70±6 68±10 69±9 0.913 LVMi (g/m2) 62±13 60±15 62±9 84±38 0.01 % Predicted VO2 at Peak 84 (77–109) 86 (82–94) 80 (73–88) 73 (62–91) 0.019 % Predicted VO2 at AT 55 (42–69) 61 (55–66) 49 (41–56) 46 (39–60) 0.023 RER 1.19±0.05 1.17±0.11 1.18±0.08 1.18±0.12 0.915 Resting global longitudinal strain (%) −18.8±2.1 −18.0±2.4 −17.9±1.9 −19.5±3.1 0.320 Data are presented as median an interquartile range, or mean and standard deviation. A p value of <0.05 demonstrates significance at the 95% confidence interval using the Kruskall Wallis test.Abstract 11 Graph 1 The association between eGFR and% predicted VO2. Lines represent the line of best fit and 95% confidence intervals.

10 Cardiac alterations after renal transplant; contoversies unravelled by cardiac mri

Background Successful kidney transplantation is associated with reduced cardiovascular (CV) morbidity and mortality compared to patients who remain on dialysis but is higher than in the general population. Longitudinal data reporting changes in uremic cardiomyopathy after renal transplant are conflicting; studies with echo have reported regression of left ventricular (LV) hypertrophy and improved systolic function but have not been replicated using cardiac MRI which is volume independent and does not depend on geometric assumptions. The CV response early after transplant with restoration of normal renal function have not been reported. The aim of this study was to assess changes in LV structure and function before and acutely (<8 weeks) after renal transplantation in patients with end-stage kidney disease (ESKD). Method All subjects were prospectively recruited prior to live-donor kidney transplantation. Patients had no history of CV disease or diabetes and underwent cardiac MRI pre-operatively and within eight weeks post-operatively. Stress echocardiography or a myocardial perfusion scan was performed to exclude ischaemic heart disease. Haemodialysis patients were scanned on the day after dialysis, and peritoneal dialysis patients were scanned at their dry weight. Cardiac MRI data were analysed using CVi42 (Calgary, Canada). Results In total 10 patients were studied (male gender 70%, age 45 years [30-60], dialysis 40%). Cardiac MRI data is presented in Table 1. Pre-operative studies demonstrated; median left ventricular mass 82 g/m2 with 6 patients reaching criteria for LV hypertrophy. Increased segmental wall thickness >11 mm in 8 patients. Mean LV ejection fraction (LVEF) 66%±10, only 2 patients had mild LV impairment (LVEF 50%–55%). The mean estimated glomerular filtration rate (eGFR) increased from 11 ml/min/1.73 m2 to 53 ml/min/1.73 m2 after transplantation without a change in body weight. Left ventricular and atrial volumes decreased at follow up without a change in LV mass. The reduction in indexed left ventricular diastolic volume (LVEDVi) was associated with an increase in ejection fraction (EF) (r=−0.810, p<0.001), and with an increased MAPSE (r=−0.868, p=0.001). Discussion A reduction in LV volumes acutely after renal transplantation is associated with improved prognostic markers of LV function and atrial size. Patients with ESKD are chronically fluid overloaded even at dry weigh. Cardiac MRI is the method of choice for longitudinal studies in defining the natural history of uremic cardiomyopathy after renal transplantation. Values are expressed as mean±SD or median (interquartile range). P Value <0.05 demonstrates significance in change of variable following transplantation.Abstract 10 Table 1 Cardiac MRI data for the change in left ventricular volumes, mass and function between pre-operative and follow up scan (<8 weeks post-transplant) Pre-operative Post-operative Change P Value LVEDV (ml) 167±79 72±17 −95±66 0.001 LVEDVi (ml/m2) 91±33 72±17 −19±19 0.012 LVESV (ml) 65±41 40±20 −25±29 0.025 LVESV (ml/m2) 33±20 21±9 −12±16 0.044 LV Mass (g) 160 (124 to 189) 164 (113 to 180) −9 (−25 to 9) 0.305 LV Mass Indexed (g/m2) 82 (60 to 91) 77 (64 to 94) −6 (−13 to 5) 0.185 EF (%) 66±10 72±8 6±7 0.028 MAPSE (mm) 13±2 13±3 0±4 0.813 Left Atrial Volume Indexed (ml/m2) 51±18 34±12 −14±15 0.012 Global Longitudinal Strain (%) −17.7±5.3 −17.7±1.8 −0.01±4.4 0.994 Segmental Wall Thickness (mm) 14±4 14±2 0±3 0.916 Values are expressed as mean SD or median (interquartile range). P Value >0.05 ?demonstrates significance in change of variable following transplantation.

135 Detecting Progression of Diffuse Interstitial Fibrosis in Alstrom Syndrome

Introduction Alstrom Syndrome (ALMS) is a rare inherited disorder caused by a mutation in the ALMS1 gene. The syndrome is a multi-system disorder with exaggerated features of the metabolic syndrome and although rare, provides a monogenic model for end-organ fibrosis and as a paradigm for the effects of severe metabolic syndrome. Adults with ALMS have a high risk of death from heart failure in their twenties due to a cardiomyopathy which (in the small post-mortem series available) is characterised by coarse fibrosis on histology. Our previous work has identified expansion of the extracellular space (ECV) consistent with diffuse interstitial fibrosis in over half of asymptomatic ALMS patients compared to controls. The aim of this study was to investigate the longitudinal change in ECV and assess the impact on ventricular structure and function. Methods A prospective longitudinal cohort study of patients attending the national service for ALMS at the Centre for Rare Disease in Birmingham from 2012. At referral and on annual follow up, all subjects underwent comprehensive LV and RV assessment with cardiac MRI (CMR 1.5T Siemens Avanto). The presence of diffuse interstitial myocardial fibrosis was assessed using native myocardial T1 relaxation mapping and extracellular volume (ECV) in the LV septum (MOLLI) using cvi42 (Circle Cardiovascular Imaging). Coarse replacement fibrosis was assessed using standard late gadolinium enhancement imaging. Results In total 14 patients (male gender 71%, age 28 ± 8years) had baseline and follow up data (median 1.7 [1.1–2.8] years). CMR data is presented in Table 1. The native LV myocardial T1 values and ECV were increased in the septum at basal and mid levels at follow up. Left ventricular mass increased (54 ± 9 g/m2 vs. 62 ± 12 g/m2) but with a reduction in septal myocardial intracellular volume (ICV 0.74 ± 0.06 vs. 0.68 ± 0.04, p < 0.05) suggesting ECV expansion rather than myocyte hypertrophy was the driver. There were no differences in LV or RV volumes or RVEF. Four patients had LGE; two patients had focal at RV insertion points LGE and two patients had mid-wall LGE in the basal infero-lateral segments. Conclusion ALMS is associated with increases in ECV and progressive change in T1 values over time that reflects progression of diffuse interstitial fibrosis in asymptomatic adults. Cross-sectional studies have identified ECV as a biomarker of cardiovascular “vulnerability” but longitudinal tracking has the potential to highlight those at greatest risk.Abstract 135 Table 1 Baseline and Follow-up CMR data Baseline Follow-up LV Septal T1 (ms) 952 (80) 1040 (1070)** LV Basal septal T1 (ms) 953 (63) 1042 (76)** LV Mid septal TI (ms) 949 (68) 1033 (58)** Septal ECV 0.26 (0.06) 0.32 (0.04)* LV EDVi (ml/m2) 57 (10) 56 (10) LVESV(ml/m2) 20 (7) 20 (8) LVEF (%) 65 (8) 67 (5) LV Mass index 54 (9) 62 (12) RVEDV(ml/m2) 57 (10) 56 (12) RVESV(ml/m2) 23 (6) 21 (6) RVEF(ml/m2) 61 (7) 63 (7) Mean (SD), ** p<0.01