Fabry cardiomyopathy Towards early diagnosis and rational follow-up Mohamed El Sayed
Colofon Fabry cardiomyopathy, towards early diagnosis and rational follow-up Dissertation, University of Amsterdam, The Netherlands Copyright © M. El Sayed, 2023 All rights reserved. No part of this publication may be reproduced or transmitted by any means, without written permission of the author. The copyrights of articles in this thesis are retained by the authors or transferred to the journal where applicable. Financial support for the printing of this thesis was kindly provided by the SPHINX stichting. ISBN: 978-94-6483-052-1 Author: Mohamed El Sayed Cover: Nora Zeid Design: Dagmar Versmoren, persoonlijkproefschrift.nl Printing: Ridderprint, www.ridderprint.nl
Table of contents Chapter 1 9 General introduction and thesis outline Chapter 2 23 Influence of sex and phenotype on cardiac outcomes in patients with Fabry disease Chapter 3 61 ECG Changes During Adult Life in Fabry Disease: Results from a Large Longitudinal Cohort Study Chapter 4 111 Early echocardiography markers of Fabry cardiomyopathy identified in a multi-decade longitudinal cohort study Chapter 5 155 Early risk stratification for natural disease course in Fabry patients using plasma globotriaosylsphingosine levels Chapter 6 183 Summary and general discussion Appendices 205 Dutch summary (Nederlandse samenvatting) 206 Arabic summary 210 Contributing authors’ affiliations 213 Portfolio 215 Curriculum vitae 217 Dankwoord 218
The heart has its own language. The heart knows a hundred thousand ways to speak -Rumi-
Chapter 1 General introduction and thesis outline
10 Chapter 1 General introduction Background Fabry disease (FD) is a rare, inherited, slowly progressive X-linked lysosomal storage disorder (OMIM 301500). The worldwide prevalence is estimated at 1:40,000 to 1:117,000 in males [1]. The substantial disparity in the reported disease prevalence may be explained by variations in the definition of FD, which in some studies individuals with non-pathogenic variants or variants of unknown significance in the GLA gene are classified as having FD [2]. Mutations in the galactosidase alpha gene (GLA) are the primary cause of FD, leading to a decreased activity of the lysosomal enzyme alpha-galactosidase A (AGAL) (enzyme commission no.3.2.1.22) [3, 4]. This results in intracellular accumulation of the enzymes’ main substrate, globotriaosylceramide (Gb3) in various organs, including the vascular endothelium, kidneys, brain, peripheral nerves and heart [5-8]. Several processes may be set into motion by the increasing cellular accumulation of Gb3 and its derivative Globotriaosylsphingosine (lysoGb3), that ultimate lead to organ damage. Cardiac involvement is common in FD and can manifest as left ventricular hypertrophy (LVH) and myocardial interstitial fibrosis formation. During adulthood, symptomatic cardiac disease in the form of conduction abnormalities, arrhythmias, ischemic heart disease and heart failure may arise, ultimately leading to cardiac death in many patients [9]. Alterations in electrophysiological markers and cardiac morphology and function precede the development of clinical heart disease. Currently, the knowledge on the course of these changes and in which patients do they arise is lacking. Also, data on the age of occurrence, the progression rate and how these clinical markers are linked to clinical outcomes is limited. The main goal of this thesis is to study the cardiac manifestations of FD, the course of cardiac disease as reflected in electrophysiological and echocardiographic features in men and women with FD throughout adult life, and how they differ from the healthy population. Pathophysiology of cardiac involvement in FD Gb3 accumulates in all cardiac cell types and tissues, including myocytes, endothelial and smooth muscle cells of intramyocardial vessels and conduction tissue [10, 11]. Although Gb3 is expected to have direct toxic effects, secondary alterations of cellular processes in response to accumulation of storage material are likely to have significant pathological consequences. This theory was supported by the finding that only 1-2% of the left ventricle volume consisted Gb3 in post-autopsy cardiac material from FD patients [12]. Moreover, despite Gb3 clearance from the vascular endothelium, many patients still develop organ-
11 General introduction and thesis outline related complications whilst being treated with enzyme replacement therapy (ERT) [13, 14]. This may be partly explained by the fact that in cardiac biopsies of FD patients, treatment with ERT did not result in significant Gb3 clearance from cardiomyocytes within five months [15]. However, the pathophysiology is probably more complex, several specific hypothetical pathways, that link the Gb3 storage to the cardiac impairment in FD have been described. First, as a consequence of Gb3 accumulation, cardiomyocytes, endothelial and smooth muscle cells proliferate. This proliferation leads to an increased oxygen demand of the cardiac muscle, which cannot be met because of microvascular dysfunction caused by low nitric oxide synthase (eNOS) expression in the affected endothelial cells. The microvascular dysfunction limits capillary elasticity and resulting oxygen deficit leads to ischemia and fibrosis [16]. Second, lysosomal glycosphingolipid accumulation suppresses the autophagic processes in the cell [17]. A disturbed autophagic flux also affects mitophagy, which in turn interferes with the mitochondrial energy production, resulting in reduced activity of the respiratory chain complexes I, IV and V and further drop in cellular levels of energy-rich phosphates (e.g. ATP). This cardiac energy metabolism dysfunction and the increased oxygen demand due to LVH may result in decreased ischemic tolerance [18-20]. Third, a deficiency of alpha-galactosidase A limits the degradation of lipidic antigens. In FD, Gb3 and lysoGb3 (a water- soluble deacylated form of Gb3) act as antigens, activating NK T-cells. This leads to the secretion of pro-inflammatory factors and oxidative species, which may enhance the processes of cell damage and death [21, 22]. Lastly, Birkel et al. (2019) also found an impaired sodium and calcium channel function in FD cardiomyocytes, derived from pluripotent stem cells, with a higher and shorter action potential [23]. These findings support the hypothesis that conduction abnormalities in FD are not only explained by tissue damage and fibrosis, but that an altered ion channel expression on cell membranes may contribute to the increased electrical depolarization velocities observed in FD [24]. The phenotype and genotype of FD Because of the X-linked chromosomal inheritance of FD, men typically have more severe symptoms and are affected earlier in life than women with FD. Additionally, classical and non-classical disease phenotypes are distinguished, with substantial variations in symptomatology, organ involvement and prognosis. Classical FD is characterized by a significantly reduced or, in men (almost), absent AGAL activity. These male patients often present in childhood with typical classical symptoms, including angiokeratomas, cornea verticillata and neuropathic pain. The presence of this triad is a strong predictor for the diagnosis of classical FD, in which the majority of classical FD patients develop multiorgan involvement of the kidneys, brain and heart during late adolescence or 1
12 Chapter 1 young adulthood, which is progressive throughout adulthood [25, 26]. In women angiokeratoma are not observed, cornea verticillata and neuropathic pain are present in a subset of patients and cardiac and cerebral disease develop in average 10 years later and not all patients are affected [27, 28]. Non-classical FD patients have higher residual activity of the AGAL enzyme due to the less disruptive GLA mutations. In the non-classical patient group, involvement of only the heart is more common. The diagnosis of non-classical FD is usually made at a later age than classical FD, as it often presents with more atypical symptoms and lacks the ‘classical triad’ of FD symptoms [2931]. The abovementioned categorization by phenotype and sex is essential for prognostication, guiding treatment and follow-up. Diagnosing FD Diagnosing FD in individuals with non-classical disease and women with classical FD, which often lack Fabry specific- symptoms, can be challenging since not all GLA- gene variants cause disease [26]. Genetic testing panels may help diagnose Fabry cardiomyopathy, which can mimic hypertrophic cardiomyopathy (HCM) [32]. If there is any uncertainty regarding the pathogenicity of a GLA variant this can be assessed by biochemical and enzymatic test, segregation studies in the family and if uncertainty persists by organ imaging and biopsies [33]. A GLA variant is deemed to be pathogenic if it leads to: 1) an increased level of lysoGb3 in the range of FD patients (male and female patients) [34, 35], 2) a significantly reduced enzyme activity level (in all male patients and some female patients) and if 3) a biopsy of an affected organ showing typical zebra body inclusions in a relevant cell type or the appearance of a low native T1-value on cardiac MRI, most likely representing myocardial sphingolipid accumulation [36]. Cardiac involvement of FD Common cardiac manifestations of FD include LVH [37-40], valvular heart disease [41], myocardial fibrosis [20, 42], microvascular disease [43, 44] and conduction abnormalities [45, 46]. Clinically, Fabry cardiomyopathy is manifested by chronic heart failure with a preserved ejection fraction (HFpEF) [47], angina pectoris (often without underlying coronary artery disease) [44] and/or (supra)ventricular arrhythmias (e.g., sinus bradycardia, atrial fibrillation (AF), and (non)sustained ventricular tachycardia). Fabry patients often suffer from brady-tachycardia syndromes warranting the implantation of a pacemaker and/or implantation of a ICD to prevent acute cardiac death due to malignant arrhythmias [48]. Cardiovascular death is the most common cause of death in patients with FD [7]. Given the cardiac morbidity and mortality in FD patients, research should
13 General introduction and thesis outline be aimed at identifying cardiac involvement at an earlier stage of the disease, so that timely preventive therapy can be started. Currently, the most commonly used treatment is enzyme replacement therapy (ERT), which was introduced in 2001 [49]. ERT is an expensive and burdensome treatment. As such, being able to identify which patient needs treatment and at what time point in the development of FD manifestations is essential. These therapy initiation decisions are especially relevant in patients with non-classical FD and women with classical FD given the high disease heterogeneity in these patient groups, as only a subset of patients develops cardiovascular events with a highly variable age of onset [26, 28]. An increasing number of studies showed that initiation of Fabry specific treatment when there is myocardial fibrosis, impaired cardiac function or when clinical complications have already occurred, is less effective in preventing the progression of heart disease compared to earlier treatment initiation [5052]. These findings emphasize the need for identification of cardiac disease markers indicative of early cardiac involvement, at a stage in which structural changes of the heart have not yet occurred. In addition, knowledge of the cardiac disease course may be helpful in monitoring whether or not the progression of FD cardiomyopathy is halted by new FD-specific therapies [53]. The following description is a hypothesized three-stage model for the development of Fabry cardiomyopathy, based on the available literature, emphasizing potential biochemical, electrophysiological and echocardiographic biomarkers. However, this model is mainly based on historical cross-sectional data, where the distinction between classical and non-classical FD is not always made. 1. The accumulation phase: sphingolipids (particularly Gb3) accumulate in the cardiac tissue but clinical signs of cardiac disease are not yet present [11, 54, 55]. At which age this cardiac accumulation starts is unknown, as the youngest patient who underwent an endomyocardial biopsy published in literature was 17 years old [15]. Although the primary substrate of AGAL is Gb3, and it seems obvious that Gb3 could serve as a potential biomarker, Gb3 is often not elevated in men with non-classical FD and women with classical FD, even though these patients may develop significant cardiac pathology [56]. In contrast to Gb3, plasma concentrations of lysoGb3, are increased in all patients with FD and are stable throughout life in an untreated patient (chapter 5) and have a clear correlation with (cardiac) disease severity [25, 57, 58]. Endomyocardial biopsies are too invasive in clinical settings for patients to be used to detect early cardiac involvement. A low native T1 value on cardiac MRI (CMR) is likely a manifestation of myocardial sphingolipid overload [59, 60]. Studies correlating the low T1 values on CMR with the degree of Gb3 accumulation in histopathological examinations are lacking. Low T1 values are found in FD patients, in presence but also in absence of LVH, suggesting 1
14 Chapter 1 the detection of glycosphingolipid accumulation even prior to the hypertrophy response [59, 61, 62]. In addition to biochemical and imaging markers, early electrocardiogram (ECG) alterations, present in the accumulation phase, have been described in the literature, of which the most important (listed from most to least common) are [24, 45, 63, 64]: - A short PR- interval and P- wave duration; - QRS- and QTc prolongation; - T- wave inversion and meeting the Sokolov-Lyon or Cornell index criteria prior to the onset of LVH on cardiovascular imaging; - Complete bundle branch block, multifocal extra systoles and atrial fibrillation. Symptomatic Fabry cardiomyopathy is characterized by diastolic dysfunction of the left ventricle with normal left ventricular ejection fraction (known as heart failure with preserved ejection fraction, HFpEF) [47, 65]. Pica et al. (2014) described in FD patients with a low T1 and a normal left ventricular mass (suggestive of the accumulation phase), several early LV diastolic function alterations, including an aberrant global longitudinal strain (GLS), higher ratio of early diastolic mitral inflow velocity/ early diastolic septal tissue mitral annulus velocity (E/e’) and a larger left atrial volume index (LAVI) [61]. Abnormal GLS and E/e’ values were associated with the development of adverse cardiac events later on in the disease development [65, 66]. 2. The hypertrophy and fibrosis phase: as Gb3 accumulation progresses, the myocardium will exhibit LVH with interstitial fibrosis formation, detectable by late gadolinium enhancement (LGE) on CMR. The median age at which FD patients develop these features is 40 years for men and 50 years for women (no distinction was made between classical and non-classical patients) [67]. Interestingly, 25% of women with FD without LVH still develop myocardial fibrosis, while fibrosis in men always occurs in the presence of LVH [68]. In other conditions that can lead to cardiac hypertrophy (e.g., aortic stenosis and other genetic hypertrophic cardiomyopathies), sex differences in ventricular hypertrophy are observed, with males again having a greater tendency to develop LVH, thus this sex effect appears to be independent of the underlying pathology [69, 70]. For the FD population, this would mean that 1) the current reference values are too insensitive for the detection of mildly elevated left ventricular mass in women [71] or 2) that we should look for morphological markers of cardiac involvement other than LVH in females with FD. At this disease stage, plasma troponin and N-terminal pro b- type natriuretic peptide (NT-proBNP) also rise and levels are associated with increases in left ventricular mass and the presence of fibrosis. In addition ECG abnormalities, most likely related to LVH and fibrosis, increase (left axis deviation,
15 General introduction and thesis outline T-wave inversion and pronounced LVH voltage criteria) [67]. Besides the aforementioned echocardiographic features, HFpEF patients without FD often have elevated Tricuspid regurgitant jet velocity (TR velocity) [72]. However, this marker was found to be normal in a smaller study, including FD patients [73]. 3. The heart failure phase: as the disease progresses, myocardial fibrosis will expand throughout the heart, and the hypertrophic heart tissue will be partly replaced by atrophic tissue with further rising of the plasma troponin and NT-proBNP [67]. Secondary to the extensive cardiac fibrosis, ST-segment alterations [74] and ultimately ventricular arrhythmias [46] can occur. Endstage diastolic heart failure as well as systolic left ventricular dysfunction occur during this stage [65], with heart failure being the most common cause of death [75]. Aims and outline The above mentioned sequence of events is hypothetical and, as said, based primarily on cross- sectional studies describing the cardiac manifestations of FD. Hence the precise longitudinal course of Fabry cardiomyopathy in patient groups stratified by sex and disease phenotype has not been documented. Studying the progression of Fabry cardiomyopathy is crucial for early diagnosis and establishing rational group-specific follow-up protocols to detect complications, but also prevent over- medicalizing patients. The Amsterdam University Medical Centre (AUMC), the national referral centre for patients with FD in the Netherlands has a longitudinal clinical dataset and biobank, which are unique in both their size and the length of systematic follow-up of patients, providing detailed clinical data. To this end, we performed several longitudinal studies at the AUMC, aiming to: 1) Map the course of cardiac manifestations of FD, from pre-symptomatic phase through to complication development, in different FD patient groups (men and women, patients with classical and non-classical FD). 2) Detect electrophysiological, imaging and biochemical characteristics of FD that precede deterioration of cardiac function to be able to detect early cardiac involvement. In Chapter 2, we describe the effect of disease phenotype and sex on the occurrence of cardiac events in FD. In Chapter 3, the evolution of ECG parameters in a large population of adults with classical FD are assessed and compared to those of apparently healthy control subjects. Chapter 4 reports on the development of morphological and functional echocardiographic features 1
16 Chapter 1 of FD cardiomyopathy during adult life in classical FD patients and compares them to those of healthy control subjects. In Chapter 5, we investigated the predictive value of lysoGb3 in untreated FD patients for the (cardiac) disease course. Chapter 6 holds a summary and general discussion of this thesis.
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19 General introduction and thesis outline 39. Linhart, A., et al., Cardiac manifestations in Fabry disease. Journal of Inherited Metabolic Disease, 2001. 24(2): p. 75-83. 40. Fernández, A. and J. Politei, Cardiac Manifestation of Fabry Disease: From Hypertrophic Cardiomyopathy to Early Diagnosis and Treatment in Patients Without Left Ventricular Hypertrophy. Journal of Inborn Errors of Metabolism and Screening, 2016. 4. 41. Linhart, A., et al., New insights in cardiac structural changes in patients with Fabry’s disease. Am Heart J, 2000. 139(6): p. 1101-8. 42. Moon, J.C., et al., Gadolinium enhanced cardiovascular magnetic resonance in Anderson- Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J, 2003. 24(23): p. 2151-5. 43. Frustaci, A., et al., Microvascular angina as prehypertrophic presentation of Fabry disease cardiomyopathy. Circulation, 2014. 130(17): p. 1530-1. 44. Chimenti, C., et al., Angina in fabry disease reflects coronary small vessel disease. Circ Heart Fail, 2008. 1(3): p. 161-9. 45. Wilson, H.C., et al., Arrhythmia and Clinical Cardiac Findings in Children With Anderson- Fabry Disease. Am J Cardiol, 2017. 120(2): p. 251-255. 46. Baig, S., et al., Ventricular arrhythmia and sudden cardiac death in Fabry disease: a systematic review of risk factors in clinical practice. Europace, 2017. 47. Liu, D., et al., Association and diagnostic utility of diastolic dysfunction and myocardial fibrosis in patients with Fabry disease. Open Heart, 2018. 5(2): p. e000803. 48. Sene, T., et al., Cardiac device implantation in Fabry disease: A retrospective monocentric study. Medicine (Baltimore), 2016. 95(40): p. e4996. 49. Eng, C.M., et al., Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry’s disease. N Engl J Med, 2001. 345(1): p. 9-16. 50. Kramer, J., et al., Relation of burden of myocardial fibrosis to malignant ventricular arrhythmias and outcomes in Fabry disease. Am J Cardiol, 2014. 114(6): p. 895-900. 51. Weidemann, F., et al., Long-term effects of enzyme replacement therapy on fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation, 2009. 119(4): p. 524-9. 52. van der Veen, S.J., et al., Early start of enzyme replacement therapy in pediatric male patients with classical Fabry disease is associated with attenuated disease progression. Mol Genet Metab, 2022. 135(2): p. 163-169. 53. van der Veen, S.J., et al., Developments in the treatment of Fabry disease. J Inherit Metab Dis, 2020. 43(5): p. 908-921. 54. Linhart, A. and P.M. Elliott, The heart in Anderson-Fabry disease and other lysosomal storage disorders. Heart, 2007. 93(4): p. 528-35. 55. Desnick, R.J., Y.A. Ioannou, and C.M. Eng, α-Galactosidase A Deficiency: Fabry Disease, in The Online Metabolic and Molecular Bases of Inherited Disease, A.L. Beaudet, et al., Editors. 2014, The McGraw-Hill Companies, Inc.: New York, NY. 56. Young, E., et al., Is globotriaosylceramide a useful biomarker in Fabry disease? Acta Paediatr Suppl, 2005. 94(447): p. 51-4; discussion 37-8. 57. Nowak, A., et al., Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease. Mol Genet Metab, 2018. 123(2): p. 148-153. 1
20 Chapter 1 58. Aerts, J.M., et al., Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci U S A, 2008. 105(8): p. 2812-7. 59. Sado, D.M., et al., Identification and assessment of Anderson-Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping. Circ Cardiovasc Imaging, 2013. 6(3): p. 392-8. 60. Goldfarb, J.W., et al., T1-weighted magnetic resonance imaging shows fatty deposition after myocardial infarction. Magn Reson Med, 2007. 57(5): p. 828-34. 61. Pica, S., et al., Reproducibility of native myocardial T1 mapping in the assessment of Fabry disease and its role in early detection of cardiac involvement by cardiovascular magnetic resonance. J Cardiovasc Magn Reson, 2014. 16: p. 99. 62. Thompson, R.B., et al., T(1) mapping with cardiovascular MRI is highly sensitive for Fabry disease independent of hypertrophy and sex. Circ Cardiovasc Imaging, 2013. 6(5): p. 637-45. 63. Nordin, S., et al., Cardiac Phenotype of Prehypertrophic Fabry Disease. Circ Cardiovasc Imaging, 2018. 11(6): p. e007168. 64. Augusto, J.B., et al., The myocardial phenotype of Fabry disease pre-hypertrophy and pre- detectable storage. Eur Heart J Cardiovasc Imaging, 2020. 65. Rob, D., et al., Heart failure in Fabry disease revisited: application of current heart failure guidelines and recommendations. ESC Heart Fail, 2022. 66. Spinelli, L., et al., Does left ventricular function predict cardiac outcome in Anderson-Fabry disease? Int J Cardiovasc Imaging, 2021. 37(4): p. 1225-1236. 67. Nordin, S., et al., Proposed Stages of Myocardial Phenotype Development in Fabry Disease. JACC Cardiovasc Imaging, 2018. 68. Niemann, M., et al., Differences in Fabry cardiomyopathy between female and male patients: consequences for diagnostic assessment. JACC Cardiovasc Imaging, 2011. 4(6): p. 592-601. 69. Olivotto, I., et al., Gender-related differences in the clinical presentation and outcome of hypertrophic cardiomyopathy. J Am Coll Cardiol, 2005. 46(3): p. 480-7. 70. Treibel, T.A., et al., Sex Dimorphism in the Myocardial Response to Aortic Stenosis. JACC Cardiovasc Imaging, 2018. 11(7): p. 962-973. 71. Maceira, A.M., et al., Normalized left ventricular systolic and diastolic function by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson, 2006. 8(3): p. 417-26. 72. Pieske, B., et al., How to diagnose heart failure with preserved ejection fraction: the HFA- PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J, 2019. 40(40): p. 3297-3317. 73. Seydelmann, N., et al., High-Sensitivity Troponin: A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease. J Am Heart Assoc, 2016. 5(6). 74. Pieroni, M., et al., Cardiac Involvement in Fabry Disease: JACC Review Topic of the Week. J Am Coll Cardiol, 2021. 77(7): p. 922-936. 75. Akhtar, M.M. and P.M. Elliott, Anderson-Fabry disease in heart failure. Biophys Rev, 2018.10(4): p. 1107-1119.
21 General introduction and thesis outline 1
Chapter 2 Influence of sex and phenotype on cardiac outcomes in patients with Fabry disease Mohamed El Sayed; Alexander Hirsch; S. Matthijs Boekholdt; Laura van Dussen; Mareen Datema; Carla E.M. Hollak; Mirjam Langeveld Heart 2021;107:1889-1897 DOI: 10.1136/heartjnl-2020-317922
24 Chapter 2 Abstract Objective This study describes the influence of sex and disease phenotype on the occurrence of cardiac events in Fabry disease (FD). Methods Cardiac events from birth to last visit (median age 50) were recorded for 213 FD patients. Patients were categorized as follows: men with classical FD (n=57), men with non-classical FD (n=26), women with classical FD (n=98) and women with non-classical FD (n=32), based on the presence of classical FD symptoms, family history (men and women), biomarkers and residual enzyme activity (men). Event rates per 1000 patient years after the age of 15 years and median event- free survival (EVS) age were presented. Influence of disease phenotype, sex and their interaction was studied using Firth’s penalized Cox regression. Results The event rates of major cardiovascular events (MACE) (combined endpoint cardiovascular death (CVD), heart failure (HF) hospitalization, sustained ventricular arrhythmias (SVA) and myocardial infarction) were: 11.0 (95% CI: 6.6-17.3) in men with classical FD (EVS 55 years), 4.4 (2.5-7.1) in women with classical FD (EVS 70 years) and 5.9 (2.6-11.6) in men with non-classical FD (EVS 67 years). None of these events occurred in women with non-classical FD. Sex and phenotype significantly influenced the risk of MACE. CVD was the leading cause of death (75%) to which HF contributed most (42%). The overall rate of SVA was low (14 events in 9 patients (4%)). Conclusions Sex and phenotype greatly influence the risk and age of onset of cardiac events in FD. This indicates the need for patient group-specific follow-up and treatment.
25 Cardiac outcomes in Fabry disease Key questions What is already known on this subject? Early cardiac manifestations of FD are left ventricular hypertrophy, fibrosis formation and conduction abnormalities. As the disease progresses, cardiac complications, such as arrhythmias and heart failure, occur in a significant proportion of FD patients, yet others remain asymptomatic throughout long-term follow-up. The evolution of cardiac events and the influence of sex and disease phenotype on this trajectory has not been described previously. What might this study add? This is the first large longitudinal cohort study describing the effect of disease phenotype and sex on occurrence of cardiac events in FD. The event rates of major adverse cardiovascular events (combined endpoint cardiovascular death (CVD), heart failure (HF) hospitalization, sustained ventricular arrhythmias (SVA) and myocardial infarction) were: 11.0 in men with classical FD (95% CI: 6.6-17.3) (event free survival (EVS) 55 years), 4.4 (2.5-7.1) in women with classical FD (EVS 70 years) and 5.9 (2.6-11.6) in men with non-classical FD (EVS 67 years). None of these events occurred in women with non-classical FD. Cardiovascular death was the leading cause of death (75%) to which heart failure contributed most (42%). The overall rate of sustained ventricular arrhythmias was low (14 events in 9 patients (4%)). How might this impact on clinical practice? Cardiac care in FD should be tailored to the sex and disease phenotype of the patient and focus on early detection and treatment of heart failure. 2
26 Chapter 2 Introduction Fabry disease (FD) is a rare X-linked lysosomal storage disease that is caused by mutations in the galactosidase alpha (GLA) gene, resulting in reduced alphagalactosidase A enzyme activity [1, 2]. Accumulation of the enzyme’s substrate globotriaosylceramide (Gb3) and its derivatives is the primary trigger for damage and dysfunction of various tissues and organs, including vascular endothelium and the heart [3-5]. Due to the X-linked mode of inheritance, men are generally more severely affected and disease manifestations occur earlier compared to women. In addition, a distinction is made between classical and non-classical disease phenotype, with significant differences in onset and progression of symptoms, organ damage, and outcome between these two groups. The classical form of FD in men is characterized by greatly reduced or absent alpha-galactosidase A activity, resulting in manifestations in multiple organs, starting from late adolescence [6, 7]. Non-classical disease manifests itself later in adulthood and often affects only the heart [8-10]. Early cardiac manifestations of FD are bradycardia, shortened PR interval, low native T1 value on cardiac MRI and, in male and a subset of female patients, cardiac hypertrophy [11, 12]. As the disease progresses, conduction abnormalities (CA), supraventricular arrhythmias, ischemic heart disease, diastolic and systolic dysfunction and ultimately overt heart failure (HF), leading to cardiac death, may occur [3, 13-22]. On the other hand, a significant number of patients will remain asymptomatic, even at an advanced age [7]. Limited evidence is available on the risk and timing of cardiac manifestations and events in different patient groups (i.e. men versus women, classical versus non-classical FD phenotype) [3, 23]. It is important to generate these data, as it will guide patient-specific followup and timing of treatment initiation, risk assessment (e.g. for sudden cardiac death) and evaluation of new FD therapies that are currently in various stages of development. To answer the open questions, we performed a retrospective study in a FD cohort under follow-up at the Amsterdam UMC, which is unique in both its size, as well as the length of systematic follow-up of patients, providing detailed clinical data on cardiac outcome.
27 Cardiac outcomes in Fabry disease Methods Patient and public involvement This is an observational longitudinal retrospective study, using data from all adult patients with a definite diagnosis of FD (figure 1) that have been under follow-up at any time at the Amsterdam University Medical Centers (AUMC), the national referral center for FD patients in the Netherlands. Figure 1: Flowchart for the diagnosis and phenotype allocation in Fabry disease. 2
28 Chapter 2 Ethics The Medical Ethics Review Committee of the AUMC confirmed that the Medical Research Involving Human Subjects Act (WMO) does not apply to this study (W19-438 # 19.505), because of the retrospective character of this study, using historical data obtained in context of regular patient care. The study was conducted in accordance with the Declaration of Helsinki. Data collection Patients were divided into 4 groups: men with classical FD, men with nonclassical FD, women with classical FD and women with non-classical FD, based on the presence of classical FD symptoms (cornea verticillata, acroparesthesia or angiokeratoma), family history or known mutation-phenotype associations (men and women) and biomarkers and residual alpha-galactosidase A activity (men) [24] (see figure 1 for details). Patients attended the clinic for standardized follow-up visits. Between September 2018 and January 2019, all available patients charts, clinical letters, cardiac imaging reports from birth until the last outpatient clinic visit were investigated to record the following events: cardiovascular death (CVD), HF hospitalization, sustained ventricular arrhythmias (SVA), myocardial infarction (MI), CA, pacemaker or implantable cardiac defibrillator (ICD) implantation, atrial fibrillation (AF), coronary artery disease (CAD), percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery, systolic dysfunction on cardiac MRI or if unavailable on echocardiography, left ventricular outflow tract (LVOT) obstruction, moderate or severe valve disease and other heart surgery/intervention. The combined endpoint major adverse cardiovascular event (MACE) was defined as the occurrence of at least one of the following events: CVD, HF hospitalization, SVA or MI. SVA included sudden cardiac death (SCD), sudden cardiac arrest, sustained ventricular tachycardia lasting >30 sec, appropriate ICD shock, and ventricular fibrillation. CA were defined as a composite of second-degree atrioventricular block type II, third- degree atrioventricular block, sinusarrest and device implantation for CA. Endpoint definitions are provided in supplemental table 1. Events were adjudicated by a panel of experts consisting of 2 cardiologists (AH and SMB) and 1 metabolic specialist (ML). Statistical analysis For all cardiac events, the event rate per 1000 patient-years was calculated in order to correct for unequal follow-up duration between the different patient groups. The corresponding 95% confidence intervals (CI) were reported for both individual and composite cardiac events, using the Mid-P exact test (table 2, supplemental table 2). For the event rates calculation, follow-up duration from
29 Cardiac outcomes in Fabry disease the age of 15 years onwards was used, because this study shows that cardiac events do not occur before the age of 15 (figure 2, table 2, supplemental table 2) and the event-free follow-up duration of especially the younger men with classical FD would impact unevenly on the event rate without this correction. Event-free survival was analyzed using the Kaplan-Meier (KM) method in which patients where stratified according to phenotype and sex. If less than 50% of the patients developed a specific event, the median age of onset for those patients that experienced the event was reported instead. Pair-wise comparison between FD patient groups was performed using a log-rank test, with Bonferroni correction. Next, these analysis were performed correcting for competing risks (CR) (e.g. non- cardiovascular death for the outcome of cardiovascular death, supplemental figures 2-6). Cox regression analyses were performed to assess the effect of phenotype and sex and the interaction between these variables on the occurrence of events. Since no events occurred in the subgroup of women with non-classical FD, we used Firth’s penalized Cox regression to obtain stable models. P values <0.008 (after Bonferroni correction) were considered statistically significant. SPSS (v.25) and R (version 3.6.1) were used for statistical analysis. Results 213 patients were included: 57 (27%) men and 98 (46%) women with classical FD, 26 (12%) men and 32 (15%) women with non-classical FD. Median age at last outpatient visit or death was 50 years (range 19-83). Patients characteristics are described in table 1. Figure 2 shows the occurrence of cardiac events for all patients in the 4 different groups. 2
30 Chapter 2 Table 1: Patient characteristics All Men Women Classical Non-classical Classical Non-classical General Number of patients, n (%) 213 (100%) 57 (27%) 26 (12%) 98 (46%) 32 (15%) Age at last outpatient visit or death (years), median (range) 50 (19-83) 45 (19-66) 64 (26-78) 51 (19-83) 47 (23-79) Cumulative follow up from age of 15 (years) 7090 1546 1190 3213 1140 Age at first outpatient clinic visit (years) median (range) 42 (3-77) 30 (3-58) 60 (22-70) 41 (7-71) 44 (19-77) Comorbidities Number of patients with CVA at any time, n (%) 25 (12%) 9 (16%) 5 (19%) 11 (11%) 0 (0%) Obesity†, n (%) 30/198 (15%) 1/51 (2%) 4/24 (17%) 16/93 (17%) 9/30 (30%) Smoking†, n (%) 75/177 (42%) 17/44 (39%) 14/23 (61%) 35/87 (40%) 9/23 (39%) Hypertension†, n (%) 48/199 (24%) 8/51 (16%) 11/26 (42%) 18/95 (19%) 11/27 (41%) Dyslipidemia†, n (%) 14/187 (8%) 0/43 (0%) 7/23 (30%) 5/91 (6%) 2/30 (7%) Diabetes mellitus†, n (%) 4/203 (2%) 0/52 (0%) 2/25 (8%) 1/96 (1%) 1/30 (3%) Cardiac imaging Echocardiography Available echocardiography at any time, n (%) 181 (85%) 49 (86%) 21 (81%) 87 (89%) 24 (75%) Left ventricular hypertrophy on echocardiography at any time, n (%)* 90/181 (50%) 24/49 (49%) 16/21 (76%) 43/87 (49%) 7/24 (29%) Cardiac MR** Available cardiac MR at last follow-up, n (%) 141 (66%) 41 (72%) 11 (42%) 71 (73%) 18 (56%) Left ventricular ejection fraction (%), median (range) 61 (24-84) 57 (24-70) 57 (48-67) 63 (51-84) 61 (57-70) Available cardiac MR, where myocardial fibrosis was assessed by late gadolinium enhancement, n (%) 139/141 (99%) 39/41 (95%) 11/11 (100%) 71/71 (100%) 18/18 (100%) Myocardial fibrosis on cardiac MR, n (%) 54/139 (39%) 13/39 (33%) 6/11 (55%) 29/71 (41%) 6/18 (33%)
31 Cardiac outcomes in Fabry disease Table 1: Patient characteristics (continued) All Men Women Classical Non-classical Classical Non-classical ERT Patients on ERT, n (%) 128 (60%) 47 (83%) 12 (46%) 62 (63%) 7 (22%) Age start ERT (years), median (range) 42 (10-77) 27 (10-58) 59 (20-68) 46 (16-71) 60 (30-77) Untreated patients, n (%) 85 (40%) 10 (17%) 14 (54%) 36 (37%) 25 (78%) Reasons for not starting ERT Diagnosis through family screening, absent or minimal organ involvement, n (%) 41 (19%) 1 (2%) 3 (12%) 17 (17%) 20 (63%) Diagnosis not through family screening, absent or minimal organ involvement, n (%) 2 (1%) 0 (0%) 0 (0%) 1 (1%) 1 (3%) Advanced disease stage, n (%) 18 (9%) 2 (4%) 9 (35%) 5 (5%) 2 (6%) Follow-up ended before ERT was available, n (%) 8 (4%) 5 (9%) 0 (0%) 3 (3%) 0 (0%) Other, n(%) 16 (8%) 2 (4%) 2 (8%) 10 (10%) 2 (6%) CVA=cerebrovascular accident; ERT=enzyme replacement therapy, MR= magnetic resonance * Definition of cardiac hypertrophy on echocardiography: (Males >51 g/m2.7 and females >48 g/m2.7), calculated with the Devereux formula: 0.8{1.04[([LVEDD + IVSd +PWd]3 - LVEDD3)]} + 0.6. LVEDD: LV end diastolic dimension (mm), IVSd: Interventricular septal thickness at end- diastole (mm), PWd: Posterior wall thickness at end- diastole (mm). ** The included cardiac MRI’s were obtained at the time of the last follow-up (with a maximum range of 2 year between the MRI and the last follow-up date). Severely affected FD patients with a non-MRI compatible cardiac device were not included in the routine imaging follow-up. † cardiovascular risk factors assessed at first outpatient clinic visit: - Obesity: Body Mass Index ≥ 30 kg/m2 - Smoking: patients who have ever smoked - Hypertension: antihypertensive medication use or systolic blood pressure of >140 mmHg and/ or diastolic blood pressure of >90 mmHg, measured at least twice - Dyslipidemia: elevated levels of total cholesterol (>6.5 mmol/l) or low density lipoprotein (LDL) cholesterol (>2.5 mmol/l) or triglycerides (>3.0 mmol/l) , or low levels of high-density lipoprotein (HDL) cholesterol (men: <1.0 mmol/l, women <1.2 mmol/l), or medication prescribed for the indication dyslipidemia - Diabetes mellitus: type I or type II if reported by a medical doctor in the medical chart or when the patient is using anti-diabetic medication. 2
32 Chapter 2 Table 2: Prevalence, event rates, and age at onset of death and cardiovascular events All (213) Men (83) Women (130) Classical (57) Non-classical (26) Classical (98) Non-classical (32) Death Number of patients, n (%) 24 (11%) 15 (26%) 3 (12%) 6 (6 %) 0 (0%) Deaths per 1000 person years (from the age of 15), with 95%-CI 3.4 (2.2-5.0) 9.7 (5.7-15.6) 2.5 (0.6-6.9) 1.9 (0.8-3.9) 0 (-) Age at death (years), median (range) 58 (26-77) 56 (26-66) 65 (64-68) 72 (57-77) (-) Cause of death: heart failure, n (%) 10 (42%) 4 (27%) 2 (67%) 4 (67%) 0 (0%) Cause of death: myocardial infarction, n (%) 2 (8%) 2 (13%) 0 (0%) 0 (0%) 0 (0%) Cause of death: ischemic or hemorrhagic cerebrovascular accident, n (%) 4 (17%) 2 (13%) 0 (0%) 2 (33%) 0 (0%) Cause death: sudden cardiac death during hemodialysis 2 (8%) 2 (13%) 0 (0%) 0 (0%) 0 (0%) Cause death: other, n (%) 6 (25%) 5 (33%) 1 (33%) 0 (0%) 0 (0%) Major adverse cardiovascular events¥ Number of patients 38 (18%) 17 (30%) 7 (27%) 14 (14%) 0 (0%) Event rate, with 95%-CI 5.4 (3.9-7.3) 11.0 (6.6-17.3) 5.9 (2.6-11.6) 4.4 (2.5-7.1) 0 (-) Age at first event 54 (33-75) 52 (33-66) 64 (34-67) 54 (34-75) (-) Cardiovascular death Number of patients 18 (9%) 10 (18%) 2 (8%) 6 (6 %) 0 (0%) Event rate, with 95%-CI 2.5 (1.6-3.9) 6.5 (3.3-11.5) 1.7 (0.3-5.6) 1.9 (0.8-3.9) 0 (-) Age at CVD 58 (47-77) 55 (47-66) 66 (65-68) 72 (57-77) (-) Heart failure hospitalization Number of patients 18 (9%) 8 (14%) 4 (15%) 6 (6%) 0 (0%) Event rate, with 95%-CI 2.5 (1.6-3.9) 5.2 (2.4-9.8) 3.4 (1.1-8.1) 1.9 (0.8-3.9) 0 (-) Age at first event 63 (43-77) 54 (43-66) 68 (64-69) 69 (52-77) (-)
33 Cardiac outcomes in Fabry disease Table 2: Prevalence, event rates, and age at onset of death and cardiovascular events (continued) All (213) Men (83) Women (130) Classical (57) Non-classical (26) Classical (98) Non-classical (32) Sustained ventricular arrhythmias ‡ Number of patients 9 (4%) 4 (7%) 3 (12%) 2 (2%) 0 (0%) Event rate, with 95%-CI 1.3 (0.6-2.3) 2.6 (0.8-6.2) 2.5 (0.6-6.9) 0.6 (0.1-2.6) 0 (-) Age at first event 56 (46-73) 48 (46-56) 67 (64-67) 62 (51-73) (-) Myocardial infarction Number of patients 22 (10%) 8 (14%) 4 (15%) 10 (10%) 0 (0%) Event rate, with 95%-CI 3.1 (2.0-4.6) 5.2 (2.4-9.8) 3.4 (1.1-8.1) 3.1 (1.6-5.6) 0 (-) Age at first event 51 (33-75) 51 (33-58) 57 (34-67) 51 (34-75) (-) Conduction abnormalities § Number of patients 29 (14%) 7 (12%) 8 (50%) 12 (12%) 2 (6%) Event rate, with 95%-CI 4.1 (2.8-5.8) 4.5 (2.0-9.0) 6.7 (3.1-12.8) 3.7 (2.0-6.4) 1.8 (0.3-5.8) Age at first documentation 60 (48-74) 56 (48-60) 62 (50-65) 63 (49-74) 72 (71-72) Atrial fibrillation Number of patients 44 (21%) 20 (35%) 7 (27%) 16 (16%) 1 (3%) Event rate, with 95%-CI 6.2 (4.6-8.3) 12.9 (8.1-19.6) 5.9 (2.6-11.6) 5.0 (3.0-7.9) 0.9 (0.04-4.3) Age at first event 55 (18-69) 49 (18-61) 57 (34-69) 58 (47-67) 68 (-) Data in table 2 is presented as number (percentage) or median (range). All event rates are per 1000 patient years from the age of 15 onwards. ¥ Major adverse cardiac events: composite of cardiovascular death, heart failure hospitalization, sustained ventricular arrhythmias and myocardial infarction. ‡ Sustained ventricular arrhythmias: composite of sudden cardiac death, sudden cardiac arrest, sustained ventricular tachycardia including appropriate ICD shock, and ventricular fibrillation. § Conduction abnormalities: composite of second-degree AV block Mobitz II, third-degree AV block, sinusarrest, and pacemaker or implantable cardiac defibrillator device implantation for conduction abnormalities. 2
34 Chapter 2 Figure 2: The occurrence of cardiac events for all 213 FD patients, stratified by sex (♂=men, ♀=women) and phenotype. Included events are: death, cardiovascular death (CVD), heart failure (HF) hospitalization (first event), sustained ventricular arrhythmias (SVA) (first event), myocardial infarction (MI) (first event), conduction abnormalities (CA) (first recorded), and atrial fibrillation (AF) (first recorded). No event was scored if none of the predefined events was recorded at the time of the last outpatient visit. Enzyme replacement therapy Sixty percent (128/213) of the included patients were treated with enzyme replacement therapy (ERT). Decisions to initiate treatment were based on the presence of symptoms as described earlier [25] or based upon the recommendations of the European Fabry Working Group once they became available [26]. The majority of the untreated patients were either diagnosed through family screening, without signs of organ involvement at last follow-up (48% of untreated patients) or diagnosed at an advanced disease stage, at which point no benefit of ERT was to be expected (21%) (table 1). Major adverse cardiovascular events The event rate (after age 15 years) for MACE was 11.0 per 1000 patient-years (95% CI: 6.6-17.3) for men with classical FD, versus 4.4 (2.5-7.1) in women with classical FD, and 5.9 (2.6-11.6) in men with non-classical FD. None of the women with non-classical FD developed MACE. KM analysis showed a significant difference between the four subgroups (figure 3, see supplemental figure 2
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