the Role of cArdiac Inflammation, endoThelial Dysfunction, and FIbrosis in fabrY Disease
Conditions: Fabry Disease, Cardiovascular Diseases
Sponsor: Caroline Michaela Kistorp

VEK project number: 112403 / H-24052180 (Journal number) 
Date: 03-09-2024 
Protocol version 01.01.02 / Document version 01.01.02 
 
the Role of cArdiac inflammation, endoThelial dysfunction, and  
fibrosis in FabrY disease: the RATIFY study 
Project group 
- 
Caroline Kistorp1,  
- 
Niels H. Brandt-Jacobsen1, 2, 
- 
Philip Hasbak2 
- 
Niels Vejlstrup3 
- 
Redi Pecini3 
Institution 
1Department of Nephrology and Endocrinology, Center of Cancer and Organ Diseases, University 
Hospital of Copenhagen - Rigshospitalet, Copenhagen, Denmark 
2Department of Clinical Physiology and Nuclear Medicine, Center of Diagnostics, University 
Hospital of Copenhagen – Rigshospitalet, Copenhagen, Denmark 
3Department of Cardiovascular Imaging, the Heart Center, University Hospital of Copenhagen – 
Rigshospitalet, Copenhagen, Denmark 
 
Sponsor, initiator, and principal investigator 
Caroline M. Kistorp, MD, PhD, Professor, 
Department of Neprhology and Endocrinology,  
Centre of Cancer and Organ Disease, 
University Hospital of Copenhagen – Rigshospitalet 
Blegdamsvej 9 
DK-2100 Copenhagen, Denmark 
Telephone: +45 22 47 56 99 / +45 35 45 96 42 
Email: caroline.micheala.kistorp@regionh.dk 
 
Specialist registrar 
Niels Høeg Brandt-Jacobsen, MD, Ph.D, Post.doc 
 
 

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Overreaching aim 
The overall objective of this study is to investigate Fabry-related cardiomyopathy, evaluating native 
T1-mapping, coronary microvascular function, cardiac inflammation, and cardiac injury in an effort 
to improve the ability to detect disease and ease diagnostics. The study aims to achieve this by: 
1) Investigating the association between cardiac inflammation, fibrosis, and injury against the 
distribution and degree of microvascular disease in patients with Fabry disease with and 
without left ventricular hypertrophy (LVH) using cardiac magnetic resonance (CMR) imaging 
and 82Rubidium Positron emission tomography and computer tomography (82Rb-PET/CT). 
2) Using an extensive, in-depth biomarker blood panel to investigate the pathological pathways 
associated with Fabry disease and Fabry-related cardiomyopathy. 
Introduction 
Fabry disease is a rare X-linked lysosomal disorder affecting 1:58,000 in the Danish population 
(males 1:85,000; females 1:44,000) [1]. A mutation in the gene encoding the enzyme 𝛼-galA, an 
essential enzyme in normal lysosomal function, causes progressive cellular accumulation of the 
glycosphingolipids, especially globotriaosylceramide (Gb3), leading to a severe disruption of 
cellular function. Men with a classic phenotype present at an early age with no or very low 𝛼-galA-
activity and develop early multi-organ involvement, especially renal and cardiac disease, resulting 
in a severely impaired prognosis [2]. However, both men and women can be affected in the presence 
of a disease-bearing mutation [2,3]. Although often less severe, females and men with a non-classic 
phenotype also present with early organ involvement, but in a much more heterogeneous degree. 
While the classic male phenotype evidently need early initiation of therapy, the need of initiating 
treatment is less clear in females and in males with a non-classic phenotype [3]. Furthermore, 
incidence of new genetic variants of uncertain clinical significance, which could indicate a Fabry 
diagnosis, has increased due to the general implementation of genetic screening programs, especially 
in hypertrophic cardiomyopathy [4–6]. 
At present, approximately 100 patients in Denmark are diagnosed with a disease-bearing 
mutation and followed at the Danish National Fabry Centre at Copenhagen University Hospital - 
Rigshospitalet. The continuing clinical challenge of who will need and when to initiate treatment 
necessitates close observation of patients at risk and, thus, a continued search for precise, reliable 
methods able to detect early cardiac involvement. Early initiation of therapy prior to the full 
manifestation of Fabry disease has shown to impede progression while evidence suggests a late 

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initiation of treatment has reduced effects [7–10], further stressing the importance of early detection 
of Fabry cardiomyopathy and thus, early initiation of treatment. 
Cardiomyopathy in Fabry disease  
In Fabry disease, the complication of greatest prognostic impact is the cardiac manifestations, 
leading to arrhythmias, heart failure and cardiac death [2,3,11]. Although, the progressive deposition 
of Gb3 accounts for a maximum of 5% of total cardiac volume [12–14], a disproportionate 
cardiomyocyte hypertrophy, coronary wall thickening and endothelial dysfunction have been the 
general findings [12–14]. Indeed, left ventricular hypertrophy (LVH) has long been a hallmark of 
Fabry cardiomyopathy [15], however, the disproportionate relationship between a relatively small 
accumulation of Gb3 and the clinical cardiac manifestation of pronounced LVH has led to the 
proposal of the accumulation of Gb3 per se causes an early disruption of cellular function by 
pathways involving oxidative stress and inflammation [14–18]. The stress induced by Gb3 is 
believed to exacerbate left ventricular mass increase, cellular apoptosis, and causes the irreversible 
substitution of functioning tissue with reparative fibrosis.  
A key site and mechanism of stress and perhaps an early indicator of disease may, therefore, 
be found investigating changes in exchange across the vascular wall. Not only does Gb3 
accumulation cause structural changes [12–14,19], Gb3 have been shown to induce the production 
of reactive oxygen species (ROS) through important inflammatory pathways such as transforming 
growth factor (TGF) β-dependent signaling, a key step in the Fabry-related vasculopathy preceding 
fibrosis [18]. The early structural changes in endothelial structure ties directly to early endothelial 
dysfunction and detrimental changes in microvascular function [18,19]. 
Fabry-related cardiomyopathy and imaging  
As one of the most distinguishing factors of Fabry cardiomyopathy, the ability to accurately detect 
LVH is paramount. Recognizing the improved spatial resolution of CMR imaging, a shift from 
echocardiography to CMR has recently caused CMR to be recommended as part of routine clinical 
practice in supplement to echocardiography to improve detection of changes in left ventricular mass 
[15,20,21].  
However, the addition of CMR-based approach has revealed several image-derived parameters 
of interest, which may provide insight into key aspects of the underlying mechanisms of Fabry 
disease, such as ongoing Gb3 accumulation, changes in fibrotic burden, and ongoing inflammation 
in the early stages of disease [15]. In general, Fabry cardiomyopathy often presents with low native 
T1 values irrespective of the presence of LVH, which have been suggested as an indirect measure 

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of Gb3 burden [15,16,22]. In comparison, reparative fibrosis increases T1-values [15,16,22]. 
Furthermore, increased T2-values could be an indirect measure of ongoing inflammation [15–17], 
and interestingly, T2-values have been shown to decrease in concert with decreases in left 
ventricular mass following enzyme replacement therapy (ERT) [16,21]. Despite its promise, the 
overall use of T1 and T2 mapping has, however, not yet been implemented in clinical practice to 
guide clinical decision making in Fabry cardiomyopathy. 
In comparison, although PET/CT-based imaging has shown promise by detecting early Fabry-
related changes such as coronary microvascular disease (CMD), which by itself provides important 
prognostic information [23], use is limited due to radiation. However, the detection of CMD can 
elucidate on the progression of vascular endothelial dysfunction and may even be a key step in 
detecting early disease. Not only is the degree of CMD associated with the degree of LVH [24–26], 
of note, CMD seem to precede changes in left ventricular mass, as signs of CMD have been found 
irrespective of sex or the presence of LVH [24–26], suggesting its use is instrumental in detecting 
the early steps of Fabry-related cardiomyopathy. 
Heterogeneity in presentation and regional disease progression? 
In Fabry, the cardiac involvement is believed to progress diffusely throughout the myocardium, with 
symmetric LVH as a key finding. However, of note, previous reports show great regional 
heterogeneity in the measured T1- and T2-values as well as regional differences using strain analysis 
to detect functional decline [15–17,22]. Furthermore, low T1-values, believed to be a 
pathognomonic feature of Fabry-associated cardiomyopathy, has been proposed to increase and 
pseudo-normalize in tandem with disease progression and development of fibrosis, making 
measuring change over time especially important [16]. 
CMR and PET/CT separately provide global measures of fibrosis, inflammation, and 
microvascular function, therefore, the combination of modalities may explain the regional 
differences specific to the individual patient, which cannot be detecting using one approach alone. 
A combined approach may therefore provide key insights into the pathology of Fabry-associated 
cardiomyopathy – especially important in distinguishing early and late-stage disease.  
Hypothesis 
In the current study, we aim to investigate the association between inflammatory and fibrotic 
pathways and microvascular dysfunction with the presentation of Fabry cardiomyopathy to elucidate 
on the underlying mechanisms of Fabry-related cardiomyopathy, thereby further improving the 

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diagnostic approach in early disease detection, and the role of the chosen modalities in monitoring 
disease progression. 
We hypothesize patients with Fabry disease exhibit  
- 
Increased T2 values as a sign of active inflammation – a sign which will exhibit regional 
differences 
- 
Reduced native T1-values as a sign of Gb3-burden and fibrosis – a value which changes 
dependent on the presence of fibrosis 
- 
Reduced myocardial flow reserve (MFR) - a sign of microvascular dysfunction and CMD, 
which further decreases with disease progression. 
Furthermore, we hypothesize the values mentioned above are highly reliant on the presence of 
reparative fibrosis, with areas exhibiting the most pronounced impairment correlating across 
modalities. 
Participants and methods  
Study design 
A longitudinal, non-interventional cohort study and will consist of a group of patients from the 
Danish National Fabry Cohort followed at the Danish National Fabry Centre, Department of 
Neprhology and Endocrinology, Copenhagen University Hospital, Rigshospitalet. Furthermore, a 
control group of healthy age- and sex-matched individuals will be included to comprise a 
contemporary control cohort and will undergo the same program. 
Participants 
We will include 36 participants with Fabry disease previously verified by genetic testing. The Fabry 
patients will be stratified by echocardiograph-verified left ventricular hypertrophy (LVH evaluated 
as LVMi, Men/female: ≥115 / ≥95 g/m2) [27]. A control group will consist of 18 healthy age- and 
sex-matched controls without LVH. 
Inclusion and exclusion criteria 
Fabry cohort 
Inclusion criteria 
- 
Male and female individuals with a genetically-verified diagnosis of Fabry disease 
- 
≥ 18 years of age 

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- 
Able to give informed consent 
Exclusion criteria* 
- 
Any contraindication against a pharmacologically induced rest-stress PET/CT protocol 
according to local safety procedures such as acute coronary syndrome, severe 
bronchospasm, severe chronic obstructive pulmonary disease, cardiac arrhythmia. 
- 
Any contraindication for MRI according to standard checklist used in clinical routine, 
including claustrophobia or metallic foreign bodies, metallic implants, internal electrical 
devices, or permanent makeup/tattoos that cannot be declared MR compatible. 
- 
Pregnancy 
 
* Individuals with a contraindication for one of the two imaging modalities will be able to participate in the study, 
but cannot undergo the imaging protocol in question. However, the proportion of individuals who cannot undergo 
both imaging protocol are not allowed to contribute more than 20% of participants in total. 
Control cohort 
Inclusion criteria 
- 
Male and female individuals ≥ 18 years of age. 
- 
Able to give informed consent 
Exclusion criteria 
- 
A genetically-verified diagnosis of Fabry disease. 
- 
Family member to a patient with a genetically-verified diagnosis of Fabry disease 
- 
Cancer expected to influence life expectancy.  
- 
Known heart failure, previous apoplexy or previously established kidney disease. 
- 
Initiation or change of antihypertensive therapy within 3 months of enrollment. 
- 
Known LVH as evaluated on echocardiography 
- 
Any contraindication for a medicine-induced stress PET/CT protocol according to local 
safety procedures such as acute coronary syndrome, severe bronchospasm, severe chronic 
obstructive pulmonary disease, cardiac arrhythmia. 
- 
Any contraindication for MRI according to standard checklist used in clinical routine, 
including claustrophobia or metallic foreign bodies, metallic implants, internal electrical 
devices, or permanent makeup/tattoos that cannot be declared MR compatible. 
- 
Pregnancy 

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Endpoints 
Primary endpoint on 82Rb-PET/CT 
- 
A between-group difference in change in global myocardial flow reserve (MFR) evaluated by 
82Rb-PET/CT, comparing Fabry patients with controls irrespective of the presence of LVH. 
Primary endpoint on CMR 
- 
A between-group difference in change in global native T1 evaluated by MRI, comparing 
Fabry patients with controls irrespective of the presence of LVH. 
Secondary endpoints 
- 
A between-group difference in change in global myocardial flow reserve (MFR) evaluated by 
82Rb-PET/CT, comparing Fabry patients with controls accounting for the presence of LVH. 
- 
A between-group difference in change in global native T1 evaluated by MRI, comparing 
Fabry patients with controls accounting for the presence of LVH. 
- 
A between-group difference in change in global T2 values evaluated by MRI, comparing 
Fabry patients with controls accounting for the presence of LVH.  
- 
A between-group difference in change in global T2 values evaluated by MRI, comparing 
Fabry patients with controls irrespective of the presence of LVH. 
Exploratory endpoints 
Analysis on exploratory endpoints consist of both the comparison of across the observed parameters at baseline and the 
observed change over time. Furthermore, analysis are performed both irrespective of and according to LVH and 
predefined Fabry-specific subgroups. 
On 82Rb-PET/CT 
- 
A between-group difference in regional MFR evaluated by 82Rb-PET/CT according to the 17-
segment model. 
On cardiac MRI 
- 
A between-group difference in regional native T1 evaluated by MRI according to the 17-
segment model. 
- 
A between-group difference in regional native T2 values evaluated by MRI according to the 
17-segment model. 
Cross-modality comparison 
- 
An association between regional impairment in global T1, T2 and MFR and according to the 
17-segment model. 

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- 
An association between regional impairment in T1, T2, MFR, and the placement of 
irreversible reparative fibrosis detected using late-gadolinium enhancement. 
- 
An association between extent and size of irreversible reparative fibrosis detected using late-
gadolinium enhancement and total perfusion defect by Rb-PET/CT. 
Additional pre-defined endpoints of interest (Rb-PET/CT):  
Agatson score, myocardial perfusion during rest and pharmacologically induced stress, cardiac 
volumes measured on both modalities (Absolute and indexed; Left ventricular mass [LVM], end-
diastolic volume [EDV], end-systolic volume [ESV], left ventricular ejection fraction [LVEF]). 
Additional pre-defined endpoints of interest (CMR):  
Cardiac volumes (Absolute and indexed; Left ventricular mass [LVM], end-diastolic volume [EDV], 
end-systolic volume [ESV], left ventricular ejection fraction [LVEF]), Left and right ventricular 
strain analysis (longitudinal, circumferential, and radial strain), indices of diastolic function. 
Cross-modality endpoints of interest: 
Cross-modality bias and variability in the assessment of cardiac volumetry and cardiac mass with 
CMR as the reference standard. 
Predefined subgroups 
Presence of left ventricular hypertrophy, biological sex, disease severity by Mainz Severity Score 
Index (MSSI) and Fabry International Index (FPI). 
Procedures 
Imaging procedures 
82Rb-PET/CT protocol 
82Rb-PET/CT provides regional information on myocardial flow, with CMD evaluated by MFR – 
the difference between myocardial flow at rest and at pharmacologically induced stress. Regionality 
is evaluated according to the 17-segment model. A routine clinical 82Rb-PET/CT protocol will be 
performed according to local standard. Patients are to meet after a 4 hour fast, with the restriction of 
not having consumed substances containing caffeine at least 12 hours prior to scanning. 
Table 1: 82Rb-PET/CT protocol 
 
Procedures 
Sequences 
Time (app.) 
PET/CT (rest) 
- 
Scan 
10 min 

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PET/CT (stress) 
- 
Repeat scan during adenosine infusion 
(mL/kg) 
10 min 
Cardiac magnetic resonance protocol 
CMR imaging-derived values elucidating on fibrosis and inflammation provides insights on regional 
differences. Regionality is evaluated according to the 17-segment model. A routine CMR protocol 
will be performed as is standard in the current Fabry observation program followed by patients at 
the Danish National Fabry Center. Patients are to meet subsequent to a 4-hour fast, with the 
additional restriction of not having consumed substances containing caffeine 12 hours prior to 
scanning. 
Table 2: Overview of cardiac MRI protocol 
 
Procedures 
Sequences 
Time (app.) 
MRI session 
- 
Scan 
30 min 
 
- 
Scan post-contrast 
20 min 
Clinical procedures 
In addition to the imaging protocol, the participants will receive a full clinical work-up, fill out a 
questionnaire and undergo blood- and urine-sampling (Table 2). 
 
Table 2: Clinical procedures 
Procedures 
Outcome 
Semi-structured interview 
- 
Medical history, including concomitant chronic disease, 
current medication, and dietary supplements. 
- 
Alcohol, tobacco, and substance abuse 
- 
Socioeconomic status and educational background 
Clinical examination 
- 
Anthropomorphic measures (Age, height, weight, waist and hip 
circumference, body mass index [BMI, kg/m2])  
- 
Office blood pressure and pulse 
- 
Electrocardiogram 
- 
Examination as specified in the  
- 
Mainz Severity Score Index 
- 
Fabry international prognostic index 
Patient reported outcome 
- 
”Dit helbred og velbefindende” (SF-36®; Quality of life)  
Blood and urine samples 
 
Research Biobank focusing on

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- 
Heart function, inflammation, and fibrosis and cellular 
signaling in the kidney 
- 
Metabolic dysfunction 
- 
Risk markers of disease 
- 
Markers related to Fabry disease risk and progression 
Establishing a biobank of future research 
- 
Surplus biological material acquired will be kept in a biobank 
for future research. 
See table 3 for overview of biomarkers 
Medical interview and clinical examination. 
Participants will undergo a semi-structured interview to acquire relevant patient information. The 
consists of their previous medical history and their current medication, established concomitant 
disease, their use of dietary supplements, their use of alcohol, tobacco and substance abuse, their 
current employment status and choice of field, and educational background (i.e. length of education). 
They will undergo a focused clinical examination acquiring basic anthropomorphic measures 
age, height, weight, hip- and waist circumference. Furthermore, the clinical examination will consist 
of general health measures, consisting of a measurement of their office blood pressure, pulse, an 
electrocardiogram, and a physical examination specified to fulfill the elements of a modified Mainz 
Severity Score Index and the Fabry International Prognostic Index. 
Patient reported outcome 
Participants will be asked to answer a health-related questionnaire. The questionnaire is used and 
validated in Fabry disease: 
- 
The SF36 Quality of Life-questionnaire 
Blood and urine sampling 
Participants will be required to undergo standard antecubital venipuncture to sample blood. The 
amount drawn will be 300 mL at the study visit. Regarding urine sampling, participants are to 
provide a first-voided, morning urine sample. 
All samples are acquired and immediately frozen as aliquots and subsequently stored at -80 
degrees (Celsius) until the end of the trial, comprising a research biobank. The research biobank is 
to cease 6 months after last patient last visit; scheduled at 01.12.2029. At the day the research 
biobank ceases, the remaining material will be considered surplus and will be transferred to a 

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biobank of future research. Regarding the research biobank, when performing the planned analysis, 
samples are to be thawed and analyzed in immediate succession, with repeat intra- and inter-assay 
analyses to determine and validate analysis-specific variation according to local laboratory 
standards. Postponing analysis until end of study is done to minimize time-dependent variation and 
is deemed necessary as part of trial conduct. Surplus material – both blood and urine – is stored and 
kept, comprising a biobank of future research. The biobank of future research is established and kept 
in accordance with the Danish laws on Data Protection and Data Security. 
Biomarkers of interest to be analyzed on samples of blood or urine are specifically defined in 
protocol (table 5). Although all biomarkers are chosen due their prospective or established clinical 
value, further biomarkers may be necessary to be defined at a later date (e.g. omcis-based blood or 
urinary biomarker panel). If one or more biomarkers of interest are thought of post-hoc, a new 
informed consent is required and an amendment to the original protocol will be made to be accepted 
by the relevant ethical committee prior to performing the analyses. In this instance, the relevant 
ethical committee can provide dispensation regarding the need for renewed consent. Separate 
consent forms will be signed in regard to the research biobank and the biobank of future research, 
respectively (See Consent forms). 
 
Table 5: Overview of pre-specified biomarkers in research biobank 
 
Sample 
Biomarker 
Volume 
Blood sample 
Circulating biomarkers specific to Fabry’s Disease 
- 
𝛼-gal A activity in leucocytes, plasma Lyso-Gb3 and 
Gb3, and urine Gb3 
Cardiac function, fibrosis and inflammation, and cellular 
signaling in the heart  
- 
GDF-15, TGF-β, FGF-21, FGF-23, VEGF, collagens, 
TnI, hsTNT, proANP, proCNP, NT-proBNP 
Clinical biomarkers of metabolic dysfunction 
- 
fasting plasma glucose, insulin, 3-OH-hydroxybutyrate, 
HbA1c, and lipid profile. 
General biomarkers of risk deemed of clinical value 
- 
Creatinine
300 mL 
Urine sample 
Urinary excretion 
- 
urinary podocyte excretion, albumin and creatinine 
excretion
200 mL 
Study visits 
Participants eligible for inclusion in the study will be required to attend 2 study visits to participate 
in the study program at baseline and again after 3 years. 

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Statistical considerations 
Justification of sample size 
82Rb-PET/CT 
From our own experience regarding normal values on MFR on healthy individuals, a baseline mean 
MFR can be expected to be 3.7 (SD 0.8) (Unpublished). In another cohort, baseline mean MFR in 
Fabry disease has previously been reported as 1.5 (SD 0.5) [26].  
Conversely, not much is known as to the expected time-dependent change, however, a 3-year 
mean decrease of 0.5 units is deemed to be a clinically significant difference. In a prospective cohort, 
a between-group mean change of 0.5, an SD of the difference of 0.5, 80% power, a type 1 error of 
5%, the final design necessitates the inclusion of 51 participants 1:1:1 to detect a 3-year-change – 
corresponding to 17 participants in each group. 
CMR 
Previously collected data has provided scanner-specific normal values for baseline mean T1 values, 
furthermore, a 40/60 ratio of men vs women included is expected. Therefore, a healthy, age- and 
sex-matched to cohort would be expected to present with a baseline mean T1-value of approximately 
1013 ms (SD 23). Consequently, patients with Fabry disease have previously been reported to have 
a mean value in the range of 917-981 ms (SD 49-61) [16]. 
The expected time-dependent change in T1-values as a sign of progression is currently 
unknown, however, a 3-year decline of 50 ms when compared to an expected stable healthy control 
cohort is deemed to be clinically significant. Thus, in a prospective cohort, a between-group mean 
change of 50 ms, an SD of the difference of 50, 80% power, a type 1 error of 5%, the final design 
necessitates the inclusion of 51 participants 1:1:1 to detect a 3-year-change – corresponding to 17 
participants in each group. 
Additional considerations 
The primary analysis is a direct comparison between patients with Fabry and healthy controls. To 
account for incidental claustrophobia and the inability to scan using all three modalities causing an 
unexpected loss of data, we aim to include 54 participants, preferably grouped 18:18:18 participants 
(Fabry w/ LVH; Fabry w/o LVH; age- and sex-matched controls).  
The current Danish National Fabry cohort consists of a little more than 100 individuals, with 
approximately 33% believed to have a history of LVH. Therefore, a Fabry-specific study size 
consisting of 36 patients with genetically verified Fabry disease - of which 18 are expected to have 

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LVH - is deemed feasible using the proposed patient population. However, if the goal distribution 
according to the presence of LVH is determined to be impossible during the conduct of the study, 
the study will allow a skewered distribution in the Fabry cohort. 
A control cohort of 18 healthy age- and sex-matched controls included as part of the study will 
constitute a basis for an in-depth comparison on the clinical implication of the proposed biomarkers 
and the prognostic implication of change in an ultra-rare genetic disease (prevalence below 
1:50.000). This information is currently unknown; therefore, the inclusion of this group is considered 
an essential part of study conduct. 
Risks and discomforts 
There can be unexpected risks and discomforts attributable to participation in the study, which cannot 
be predicted prior to trial conduct. The following will elaborate on known risks and discomforts. 
Risks related to clinical procedures 
Blood sampling 
Venipuncture to acquire blood samples can be uncomfortable but is considered safe and performed 
as a routine procedure in standard medical practice. Although a small hematoma may occur, and a 
minimal risk of infection is present, proper technique will be applied to ensure a minimal level of 
risks. In comparison to blood donation, where 500 mL is drawn, the current study will require a 
sample of 300 mL and may induce slight, transient lightheadedness, but is otherwise not associated 
with any known risk. 
Risks related to scanning procedures 
Radiation in general 
In general, Danish citizens’ lifetime risk of cancer is approximately 25.00%. Any exposure of 
radiation is believed to cause a stochastic risk of inducing spontaneous mutation and an increase in 
incident cancer. The 82Rb-PET/CT scan delivers radiation to a much lesser degree than a single 
photon emission tomography (SPECT) scan, which is the current noninvasive clinical standard of 
diagnosing microvascular coronary artery disease. Radiation doses of 82Rb-PET/CT scans performed as 
clinical standard are approximately 4 mSv per investigation, including both rest and stress. Thus, the 
individual dose experienced by each participant would amount to 8 mSv during the study period of 3 
years. Assuming a linear relationship between radiation exposure and risk, participating in this study 

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increases the risk of cancer to approximately 25,04% (risk category: IIb) [28]. Due to the stochastic risk 
of mutation, pregnancy is a contraindication to trial participation. 
82Rb-PET/CT 
When disregarding the specific risks attributed to radiation discussed in the above, PET/CT is 
considered safe and is not related to short- or long-term risk. The infusion of adenosine can induce 
discomfort, nausea, and a transient shortness of breath. However, due to the short biological half-life 
of the drug, symptoms will disappear within seconds of terminating transfusion. If a participant 
becomes claustrophobic and wants to terminate an ongoing exam, the physician is obliged to do so. 
Cardiac magnetic resonance imaging 
If an implanted device is deemed MRI-compatible or MRI-safe and no contraindication is found, 
CMR is considered safe and is not related to short- or long-term risk. If a prospective patient has an 
implanted device which is at least MRI compatible (e.g. pacemaker), participation in the study will 
require additional safety precautions prior to and after scans are performed according to local 
standards. If a participant becomes claustrophobic and wants to terminate an ongoing exam, the 
physician is obliged to do so. The contrast-agent, Gadobutrol (Gadovist), is a paramagnetic CMR 
contrast agent and is not associated with any radiation risk. Similar contrast agents have previously 
been associated with post-contrast cutaneous manifestations in patients with a severely impaired 
kidney function receiving increased doses (eGFR < 30 mL/min/1.73m2), however, the use is safe 
among individuals with normal kidney function when receiving standard doses (0.2-0.4 mmol/kg) or 
receiving reduced doses in patients with low kidney function [29]. Injection with contrast may be 
associated a short temporary dizziness or local sense of local warming at the site of injection as a 
transient phenomenon. Patients deemed eligible to participate will receive an appropriate dose of 
contrast agent according to local safety guidelines.  
Data protection of Personal Information in the Study 
All legislations, regulations, and laws on Data Protection and Data Security and the directives of the 
Danish Protection Agency will be complied with during the conduct of the trial. Permission to handle 
personal data will be sought and approved by the Danish Data Protection Agency. All data are stored 
pseudo-anonymized and analyzed electronically and no unauthorized access to data is allowed. 
Original data is filed according to a unique participant number. REDCap, hosted by OPEN (Open 
Patient data Explorative Network) will be used for registration of clinical data. REDCap meets the 
safety requirements set by the Danish Data Protection Agency for storage of person-sensitive data; 

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prescribed medication, medical history, height, weight are examples of such data. Data will be 
encrypted and stored for 15 years in accordance with recommendations on data storage from the 
Danish Data Protection Agency and thereafter transferred to the Danish Data Archives. 
The study is reported to the Danish Data Protection Agency in Region H and will be handled 
according to the regulations of the General Data Protection Regulation: GDPR: REGULATION 
(EU) 2016/679 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 27th of April 
2016 on the protection of natural persons with regard to the processing of personal data and on the 
free movement of such data, and repealing Directive 95/46/EC and the Data Potection Act. Data is 
stored for 15 years. 
Procedures for recruiting participants and informed consent  
Initial contact 
Fabry patients are recruited from the Department of Hormone and Metabolism, Copenhagen 
University Hospital, Rigshospitalet. The department is assigned as the national center concerning 
the treatment and monitoring of patients with Fabry disease. Eligibility to participate is evaluated 
by the doctor or other personnel of the patient’s usual care at a regularly scheduled outpatient visit. 
Eligibility is evaluated using a confirmed diagnosis of Fabry disease using the current clinical 
standard and the presence of left ventricular hypertrophy, and these two parameters (i.e. the inclusion 
criteria) will be transferred to the project doctor – the presence of left ventricular hypertrophy is the 
key grouping parameter used in the project. Patients who fulfill the inclusion criteria and none of 
the exclusion criteria will be informed of the study by the personnel at the department involved in 
their usual care. By acceptance, they will receive a written patient information. If the patient favors 
contact initiated by an investigator from the study and provides oral consent, the patients contact 
information (name, email, phone number) will be forwarded to an investigator. The oral information 
for the study is then presented by a medical doctor, who is a member of the study group at the 
department, given in quiet surroundings. Individuals acting as controls in the study will be recruited 
from varies homepages (sundhed.dk, facebook, and forsoegspersonen.dk), where contact 
information on investigators can be found. The recruitment material will be reviewed and approved 
by the Ethics Committee prior to use. Potential participants can contact the Departments of 
Nephrology and Endocrinology, Copenhagen University Hospital, Rigshospitalet by email or 
telephone. Regarding advertisements on Facebook, any advertisement/post will have its ability to be 
shared or write a comment to the advertisement/post disabled. In addition to the written information 
pertaining to the study, it will be accompanied by the brochure: “Forsøgspersoners rettigheder i et 

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sundhedsvidenskabeligt forskningsprojekt” (Your rights as a participant in medical research) and 
“Dit væv, din ret” (Your tissue, your right). If the individual accepts further information on the study, 
a meeting in a quiet, undisturbed room will be scheduled with one of the investigators, and the person 
will be informed of the right to have a bystander present at that moment. The patient will be offered 
at least 24 hours reflection period before signing the consent form. The informed consent to 
participate in the study gives the research responsible doctors, sponsor and their representatives, and 
potential control authorities access to the information on kidney function, and relevant medical 
information for the study from the patient’s medical record.  
Scheduled meeting 
At the scheduled meeting, the individual will receive additional oral information, from an 
investigator, and it will be clarified whether the patient fulfill the general participation criteria. The 
patient will be informed about the terms and restrictions of the form of ‘informed written consent’. 
The investigator will ensure that the patient is adequately informed about the study background and 
design both orally and in writing. It will be made clear that the patient can withdraw from the study 
at any time without repercussions. 
Acquisition of informed consent 
If the patient is interested in participating in the study after the initial information meeting and after 
the allotted deciding time, a meeting will be scheduled where oral and written informed consent will 
be obtained. After consent to participate in the study has been obtained, the first study visit will be 
scheduled. No study-related examinations will be conducted prior the acquisition of informed 
consent. Investigators will only access electronic hospital records to transfer or record information 
after acquisition of written informed consent. 
Informed consent 
The participant will be required to sign the individual forms of informed consent applicable. 
Consent regarding study participation 
The participant’s consent includes the right to read and transfer information from electronical hospital 
records to RED-Cap by investigators. The data transferred include information such as medical 
history, blood and urine test results, prescribed and over-the-counter medication. Further, the 
informed consent includes permission to establish a research biobank regarding the analyses of 
biomarkers specified in the protocol. In addition, consent gives direct access to electronic hospital 
records for the primary investigator, the sponsor or their representatives, as well as authorized 

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auditors in order to retrieve the health-related information necessary to perform the study and to 
perform quality control and monitoring. The access to electronic hospital records gives access to 
information from previous clinical evaluations performed by doctors or other hospital staff in relation 
to hospitalizations or outpatient visits. The information accessed will be used to assist in attaining a 
contemporary assessment of the individual’s organ involvement and concomitant disease (i.e. stage 
of disease according to current clinical standard). This includes access to previously performed 
diagnostic analyses (e.g. biochemical analysis of blood, urine or other tissue samples), image-based 
evaluations (e.g. by ultrasound, computer-tomography or magnetic resonance imaging), and current 
use of prescribed medication. These sources of information are vital in order to acquire a sufficient 
image of the patient’s current medical health status. 
The informed consent will be valid for the duration of the study.  
Consent regarding establishment of a biobank of future research 
A separate form of informed consent gives permission to establish a biobank of future research 
consisting of surplus material, if any, acquired at the initial visit of the core program. The aim of the 
biobank for future research is to ensure the ability to answer contemporary research questions in a 
rapidly evolving field. Future analyses may therefore include, but not be limited to, analyses of 
circulating levels of hormones, proteins, DNA-excerpts, not specified in the current protocol. Future 
analyses will be required to be approved by a relevant regional ethics committee prior to analysis. 
The informed consent will be valid for the duration of the study.  
Time schedule 
- 
Ethics committee approval 
 
 
Q2-3, 2024 
- 
First patient first visit  
 
 
Q4, 2024 
- 
Last patient last visit  
 
 
Q2, 2029 
- 
Cessation of Research Biobank  
 
Q4.2029 
- 
End of data analysis and manuscript submission 
Q3, 2030 
Funding 
The primary investigator, sponsor and initiator of the study is professor, Caroline Kistorp from the 
department of Nefrology and Endocrinology at Copenhagen University Hospital, Denmark. The  
study will be funded by external independent private and public foundations. Any funding is 
deposited in a research account administered at Rigshospitalet, Copenhagen University Hospital - 
Rigshospitalet, Denmark. None of the investigators or departments will have any financial gain from 

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conducting the study. As funding is secured, the ethical committee (VEK) and the included patients 
will be informed, and the patient information will be accordingly updated to include the information 
on funding sources. 
Current funding sources 
- 
Unrestricted grant from Sanofi A/S: 250.000 DKK 
Patient insurance and reimbursement 
The study is conducted at the Department of Nephrology and Endocrinology, Rigshospitalet and 
covered by the departments insurance. Participants in the trial are covered by the existing patient 
insurance (”Patienterstatningen”). The participants will not receive payment. If the study requires 
extra visits to the department, transportation cost will be covered according to the guidelines for 
voluntary research subject’s appendix 1 of the National Scientific Committee (NVK) . Furthermore, 
expenses as to their nutritional need during visits will be provided for.  
Ethical considerations and clinical implications 
The study will be conducted in accordance with the Helsinki II declaration, the regulations of the 
General Data Protection Regulation, and will follow the directives of the laws on Data Security 
(‘Datasikkerhed’) and on Data Protection (‘Databeskyttelsesloven’). The study will be approved by 
the Danish Data Protection Agency and the Regional Ethics Committee of Copenhagen Denmark. 
Furthermore, the trial will be conducted following the current clinical research standard.  
Heart disease is the complication with the greatest clinical impact in Fabry disease. All 
scheduled procedures – except for 82Rb-PECT/CT – are part of the current observational program 
followed by patients at the Danish National Fabry Center. Although the addition of 82Rb-PECT/CT 
to current diagnostic standard - using echocardiography and CMR - involves exposure to radiation, 
information on endothelial dysfunction derived from 82Rb-PET/CT, we believe, is of incremental 
value in the detection of early-stage disease and would be the clinical alternative to CMR in the 
presence of an implantable pacemaker/cardioverter-defibrillator or any implantable device not 
compatible with CMR. 
When evaluated by CMR- and PET-imaging, current evidence suggests distinct differences in 
Fabry disease when compared with other conditions causing hypertrophic cardiomyopathy, 
therefore, we believe the current study will improve the diagnostic approach and add to the ability 
to detect patients in early stages of disease. Furthermor, we find that the potential therapeutic gain 

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for the participants and future patients outweigh the risks and discomforts of participating in the 
study, and therefore, we believe conducting the study is justified. 
Patient participation will depend on receiving informed oral and written consent, with 
participants reserving the right to withdraw consent at any time during trial conduct without further 
consideration. 
Dissemination of results 
The investigators oblige themselves to publish all clinically relevant findings in peer-reviewed 
journals irrespective of their ability to achieve statistical significance – i.e. publishing all results 
irrespective of being positive, neutral, or negative. Results will be published following the 
International Committee of Medical Journal Editors (ICMJE) recommendations.  
The investigators will present findings at national and international conferences with an aim to 
strengthen the current understanding of, to substantiate or challenge the current clinical approach to 
Fabry disease. Furthermore, the authors will disseminate the results of the overreaching aims among 
patients with Fabry disease through patient organizations on the national level. 
 
 

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References 
[1] 
Effraimidis G, Rasmussen ÅK, Dunoe M, Hasholt LF, Wibrand F, Sorensen SS, et al. 
Systematic cascade screening in the Danish Fabry Disease Centre: 20 years of a national 
single-centre 
experience. 
PLoS 
One 
2022;17:e0277767. 
https://doi.org/10.1371/journal.pone.0277767. 
[2] 
Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death in 
males and females with Fabry disease: Findings from the Fabry Registry. Genet Med 
2009;11:790–6. https://doi.org/10.1097/GIM.0b013e3181bb05bb. 
[3] 
Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi M, Feldt-Rasmussen U, et al. 
Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry 
Registry. Mol Genet Metab 2008;93:112–28. https://doi.org/10.1016/j.ymgme.2007.09.013. 
[4] 
Schiffmann R, Fuller M, Clarke LA, Aerts JMFG. Is it Fabry disease? Genet Med 
2016;18:1181–5. https://doi.org/10.1038/gim.2016.55. 
[5] 
Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, et al. Prevalence of 
Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. 
Circulation 2002;105:1407–11. https://doi.org/10.1161/01.CIR.0000012626.81324.38. 
[6] 
Monserrat L, Gimeno-Blanes JR, Marín F, Hermida-Prieto M, García-Honrubia A, Pérez I, et 
al. Prevalence of Fabry Disease in a Cohort of 508 Unrelated Patients With Hypertrophic 
Cardiomyopathy. 
J 
Am 
Coll 
Cardiol 
2007;50:2399–403. 
https://doi.org/10.1016/j.jacc.2007.06.062. 
[7] 
Weidemann F, Niemann M, Störk S, Breunig F, Beer M, Sommer C, et al. Long-term outcome 
of enzyme-replacement therapy in advanced Fabry disease: Evidence for disease progression 
towards 
serious 
complications. 
J 
Intern 
Med 
2013;274:331–41. 
https://doi.org/10.1111/joim.12077. 
[8] 
Weidemann F, Niemann M, Breunig F, Herrmann S, Beer M, Störk S, et al. Long-term effects 
of enzyme replacement therapy on fabry cardiomyopathy. Evidence for a better outcome with 
early 
treatment. 
Circulation 
2009;119:524–9. 
https://doi.org/10.1161/CIRCULATIONAHA.108.794529. 
[9] 
Pieroni M, Camporeale A, Bona R Della, Sabini A, Cosmi D, Magnolfi A, et al. Progression 
of fabry cardiomyopathy despite enzyme replacement therapy. Circulation 2013;128:1687–8. 
https://doi.org/10.1161/CIRCULATIONAHA.113.002799. 
[10] Rombach SM, Smid BE, Bouwman MG, Linthorst GE, Dijkgraaf MGW, Hollak CEM. Long 
term enzyme replacement therapy for Fabry disease: Effectiveness on kidney, heart and brain. 
Orphanet J Rare Dis 2013;8:1–9. https://doi.org/10.1186/1750-1172-8-47. 
[11] Patel V, O’Mahony C, Hughes D, Rahman MS, Coats C, Murphy E, et al. Clinical and genetic 
predictors of major cardiac events in patients with Anderson-Fabry Disease. Heart 
2015;101:961–6. https://doi.org/10.1136/heartjnl-2014-306782. 
[12] Linhart A, Elliott PM. The heart in Anderson-Fabry disease and other lysosomal storage 
disorders. Heart 2007;93:528–35. https://doi.org/10.1136/hrt.2005.063818. 
[13] Yogasundaram H, Kim D, Oudit O, Thompson RB, Weidemann F, Oudit GY. Clinical 
Features, Diagnosis, and Management of Patients With Anderson-Fabry Cardiomyopathy. Can 
J Cardiol 2017;33:883–97. https://doi.org/10.1016/j.cjca.2017.04.015. 
[14] Frustaci A, Chimenti C, Doheny D, Desnick RJ. Evolution of cardiac pathology in classic 
Fabry disease: Progressive cardiomyocyte enlargement leads to increased cell death and 
fibrosis, and correlates with severity of ventricular hypertrophy. Int J Cardiol 2017;248:257–
62. https://doi.org/10.1016/j.ijcard.2017.06.079. 

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[15] Esposito R, Santoro C, Mandoli GE, Cuomo V, Sorrentino R, La Mura L, et al. Cardiac 
imaging in anderson-fabry disease: Past, present and future. J Clin Med 2021;10. 
https://doi.org/10.3390/jcm10091994. 
[16] Nordin S, Kozor R, Vijapurapu R, Augusto JB, Knott KD, Captur G, et al. Myocardial Storage, 
Inflammation, and Cardiac Phenotype in Fabry Disease after One Year of Enzyme 
Replacement 
Therapy. 
Circ 
Cardiovasc 
Imaging 
2019;12:1–9. 
https://doi.org/10.1161/CIRCIMAGING.119.009430. 
[17] Nordin S, Kozor R, Bulluck H, Castelletti S, Rosmini S, Abdel-Gadir A, et al. Cardiac Fabry 
Disease With Late Gadolinium Enhancement Is a Chronic Inflammatory Cardiomyopathy. J 
Am Coll Cardiol 2016;68:1707–8. https://doi.org/10.1016/j.jacc.2016.07.741. 
[18] Choi J Bin, Seol DW, Do HS, Yang HY, Kim TM, Byun YG, et al. Fasudil alleviates the 
vascular endothelial dysfunction and several phenotypes of Fabry disease. Mol Ther 
2023;31:1002–16. https://doi.org/10.1016/j.ymthe.2023.02.003. 
[19] Pollmann S, Scharnetzki D, Manikowski D, Lenders M, Brand E. Endothelial Dysfunction in 
Fabry Disease Is Related to Glycocalyx Degradation. Front Immunol 2021;12:1–13. 
https://doi.org/10.3389/fimmu.2021.789142. 
[20] Hazari H, Belenkie I, Kryski A, White JA, Oudit GY, Thompson R, et al. Comparison of 
Cardiac Magnetic Resonance Imaging and Echocardiography in Assessment of Left 
Ventricular 
Hypertrophy 
in 
Fabry 
Disease. 
Can 
J 
Cardiol 
2018;34:1041–7. 
https://doi.org/10.1016/j.cjca.2018.03.011. 
[21] Perry R, Shah R, Saiedi M, Patil S, Ganesan A, Linhart A, et al. The Role of Cardiac Imaging 
in the Diagnosis and Management of Anderson-Fabry Disease. JACC Cardiovasc Imaging 
2019;12:1230–42. https://doi.org/10.1016/j.jcmg.2018.11.039. 
[22] Sado DM, White SK, Piechnik SK, Banypersad SM, Treibel T, Captur G, et al. Identification 
and assessment of anderson-fabry disease by cardiovascular magnetic resonance noncontrast 
myocardial 
T1 
mapping. 
Circ 
Cardiovasc 
Imaging 
2013;6:392–8. 
https://doi.org/10.1161/CIRCIMAGING.112.000070. 
[23] Aljizeeri A, Ahmed AI, Suliman I, Alfaris MA, Elneama A, Al-Mallah MH. Incremental 
prognostic value of positron emission tomography-derived myocardial flow reserve in patients 
with and without diabetes mellitus. Eur Hear J - Cardiovasc Imaging 2023;24:563–71. 
https://doi.org/10.1093/ehjci/jead023. 
[24] Spinelli L, Giudice CA, Riccio E, Castaldo D, Pisani A, Trimarco B. Endothelial-mediated 
coronary flow reserve in patients with Anderson-Fabry disease. Int J Cardiol 2014;177:1059–
60. https://doi.org/10.1016/j.ijcard.2014.11.026. 
[25] Cecchi F, Tomberli B, Olivotto I, Castelli G, Sciagrà R, Berti V, et al. Coronary microvascular 
dysfunction is an early feature of cardiac involvement in patients with Anderson-Fabry disease. 
Eur J Heart Fail 2013;15:1363–73. https://doi.org/10.1093/eurjhf/hft104. 
[26] Tomberli B, Cecchi F, Sciagrà R, Berti V, Lisi F, Torricelli F, et al. Coronary microvascular 
dysfunction is an early feature of cardiac involvement in patients with Anderson–Fabry 
disease. Eur J Heart Fail 2013;15:1363–73. https://doi.org/10.1093/eurjhf/hft104. 
[27] Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. 
Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An 
Update from the American Society of Echocardiography and the European Association of 
Cardiovascular 
Imaging. 
J 
Am 
Soc 
Echocardiogr 
2015;28:1-39.e14. 
https://doi.org/10.1016/j.echo.2014.10.003. 
[28] Appendiks 2. Retningslinjer om anvendelse af ioniserende stråling i sundhedsvidenskabelige 
forsøg. Den Natl Vidensk Komité 2011;2:2–4. 
[29] Khawaja AZ, Cassidy DB, Al Shakarchi J, McGrogan DG, Inston NG, Jones RG. Revisiting 

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the risks of MRI with Gadolinium based contrast agents—review of literature and guidelines. 
Insights Imaging 2015;6:553–8. https://doi.org/10.1007/s13244-015-0420-2. 
 
 

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Overview of Appendix 
- 
Informed consent form 
o Participation in study (Patient with Fabry) 
o Participation in study (Healthy control) 
o Biobank of future research 
- 
Documentation of Primary 
- 
Curriculum Vitae of Primary 
- 
Participant information 
- 
Information Pamphlets 
o “Forsøgspersonens rettigheder i et sundhedsvidenskabeligt forskningsprojekt” 
o “Dit væv, din ret” 
- 
Questionnaires 
o SF-36 Quality of Life questionnaire