Biomarkers and Epigenetic Markers Associated With Pain in Patients With Symptomatic Atrial Fibrillation Compared With Controls
Conditions: Atrial Fibrillation
Sponsor: Region Örebro County

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Biomarkers and epigenetic markers associated with pain in patients 
with symptomatic atrial fibrillation compared with controls 
 
 
 
Correspondence: 
Anna Björkenheim, MD, PhD 
 
Ole Fröbert, MD, PhD 
Department of Cardiology  
 
Department of Cardiology 
Örebro University Hospital 
 
Örebro University Hospital 
701 85 Örebro, Sweden 
 
 
701 85 Örebro, Sweden 
Telephone +46 19 602 54 59 
 
Telephone +46 602 54 13 
Fax +46 19 602 24 07 
 
 
Fax +46 19 602 54 38 
Email: anna.bjorkenheim@regionorebrolan.se 
Email: ole.frobert@regionorebrolan.se 
 
 

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Abstract 
Background 
Atrial fibrillation (AF) is the most common sustained arrhythmia and the number of patients 
with AF is expected to increase substantially in the coming decades. One third of patients 
with AF report no AF-associated symptoms, but up to one-fourth report severe symptoms. It 
is unclear why patients’ experience of AF-related symptoms varies so much. We have 
previously shown that patients with symptomatic AF exhibit lower pain tolerance than 
patients with asymptomatic AF, as well as impaired pain inhibitory control and facilitated 
summation of pain, indicating that pain sensitisation may be of importance in symptomatic 
AF. In patients with chronic pain conditions, several biomarkers and epigenetic markers 
associated with generation and /or maintenance of chronic pain have been identified. 
Previous research of biomarkers and epigenetic markers associated with pain is sparse in 
patients with AF.  
Objective and methods 
To study levels of biomarkers and epigenetic markers in blood in patients with symptomatic 
paroxysmal AF (n=100), in relation to severity of AF symptoms, and compared to age- and 
sex-matched controls without AF (n=100). Blood will be obtained before and after AF 
ablation and levels of biomarkers, epigenetic markers and cardiac and inflammatory 
markers, analysed. Patients will complete an AF-specific symptom and a generic health-
related quality of life questionnaire.  
Clinical relevance 

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In the future, biomarkers and epigenetic markers associated with pain may be used as a tool 
for evaluation of patients with AF and have an impact on individualized management. 
Another possibility is a rationale for future studies of novel analgesics that neutralize 
biomarkers or antagonizes its receptors. 
Trial Registration 
The study protocol will be registered at ClinicalTrials.gov after approval by the Swedish 
Ethical Review Authority. 
Keywords 
Atrial fibrillation, Symptoms, Quality of life, Pain 
 
 

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Abbreviations 
AF 
 
Atrial fibrillation 
AF6 
 
Atrial fibrillation 6 questionnaire 
DNA 
 
Deoxyribonucleic acid 
 
ECG 
 
Electrocardiogram 
NGF 
 
Nerve growth factor 
RNA 
 
Ribonucleic acid 
SF-36 
 
Short form 36 health survey 
 
 
 

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Introduction 
Atrial fibrillation 
Atrial fibrillation (AF) is the most common sustained arrhythmia affecting approximately 3% 
of adults aged 20 years or older in Western countries, and is expected to increase further in 
the coming decades(1). The presence of AF is independently associated with an increased 
risk of all-cause mortality and morbidity, largely due to stroke and heart failure, dementia, 
symptoms, and impaired quality of life(2-7). The management of AF aims to prevent AF-
related complications using oral anticoagulation therapy in patients with a high risk of stroke 
and to reduce symptoms and improve health-related quality of life using a rate (slowing of 
the ventricular rate) or rhythm control (restoration and maintenance of normal sinus 
rhythm) strategy(8). 
About one third of patients with AF have no AF-associated symptoms, but up to one-fourth 
of patients report severe symptoms such as palpitations, dyspnea, chest discomfort or pain, 
dizziness and syncope(9-11). In addition, one third of patients with symptomatic AF suffer 
from psychological distress(11, 12). It is well recognized, but unclear why patients’ 
perception of AF varies so much. Several studies have evaluated the relationship between 
patient characteristics and the presence of AF symptoms and have found that symptomatic 
AF is more frequent in women than in men, and in younger age(13, 14). Inconsistent results 
have been reported for associations between symptomatic AF and comorbidities(15). 
Furthermore, symptoms are more common in patients with paroxysmal and persistent AF 
than in patients with permanent AF(16). However, asymptomatic AF episodes are common 
even in highly symptomatic patients and AF interventions such as AF ablation increase 
asymptomatic episodes(17). In conclusion, little is known of the pathophysiological 

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mechanisms underlying AF symptomatology but both somatic and psychological factors are 
likely involved. 
Pain mechanisms 
Patients with chronic pain conditions such as osteoarthrosis, chronic pancreatitis and 
irritable bowel syndrome, show a high degree of central sensitisation, i.e. facilitated pain 
responses to repeated painful stimulation and impaired conditioned pain modulation (CPM) 
compared with controls(18-21). Furthermore, these patients often show a discrepancy 
between pain intensity and objective measures of disease severity and healthcare personnel 
often underestimate patients’ pain intensity(22, 23). It is also well-known that stress 
influences pain sensitivity and has been correlated to hyperalgesia in patients with ischemic 
heart disease(24, 25). The importance of pain sensitisation in visceral ailments such as AF is 
emerging, and the authors have previously shown that patients with symptomatic 
permanent AF exhibit both impaired pain inhibitory control as well as facilitated summation 
of pain, and therefore, pain sensitisation(26). 
Biomarkers 
Biomarkers associated with chronic pain, such as nerve growth factor (NGF), are proteins 
fundamental during embryonal development for the growth, differentiation, and survival of 
sensory and sympathetic afferent neurons. During adulthood, they have been found to play 
a key role in the modulation of nociception through short- (direct sensitisation of peripheral 
nociceptors) and long-term (changes of gene expression in the dorsal root ganglion) effects. 
These modifications lead to a wider input from peripheral nociceptors resulting in increased 
signaling to the central nervous system(27), (28). AF ablation has been shown to increase the 
plasma level of NGF in humans in the days following the procedure(29), and chronic high 

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levels of NGF and noradrenaline increased the incidence of inducible AF and its duration in 
animal studies(30). The use of monoclonal NGF antibodies has been administered to patients 
with osteoarthritis, providing a significantly greater pain relief compared to NSAIDs and 
opioids(31). 
Epigenetic markers 
Epigenetic mechanisms such as DNA methylation, covalent histone modifications, and non-
coding RNAs, have been observed to play an important role as mediators of long-term 
changes in central and peripheral nervous systems in chronic pain. Epigenetic markers can 
be measured in blood or tissue(36-37). To our knowledge, pain-related epigenetic markers 
have not been analysed in patients with AF. 
 
Purpose 
To study levels of biomarkers and epigenetic markers associated with pain as well as cardiac 
and inflammatory biomarkers in patients with symptomatic paroxysmal AF, in relation to 
severity of AF symptoms, and compared to age- and sex-matched controls without AF. 
 
Hypothesis 
We hypothesize that 
1. Biomarkers and epigenetic markers increase with AF severity 
2. Patients with symptomatic AF display increased levels of biomarkers compared with  
controls, thereby further proving the involvement of central sensitisation 
mechanisms in patients with symptomatic AF 

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Clinical relevance 
In the future, biomarkers and epigenetic markers associated with pain could be used as tools 
for evaluation of patients with AF, and have an impact on individualized patient 
management. Treatment may include medication that neutralizes the biomarker or 
antagonizes its receptors. 
 
Material and methods 
Study design 
Single-center cohort study, Örebro University Hospital. 
 
Subject inclusion criteria 
Consecutive study participants will be recruited from the waiting list of all patients planned 
for AF ablation (pulmonary vein isolation) in Örebro University Hospital. Only patients with 
symptomatic AF are planned for AF ablation. 
Further inclusion criteria: 
- 
Male or female subject ≥ 20 years and ≤ 75 years 
- 
Paroxysmal AF (AF that terminates spontaneously or with intervention within 7 days 
(8)) 
- 
Written informed consent 
Subject exclusion criteria 
- 
Persistent AF (AF that is continuously sustained beyond 7 days, including episodes 
terminated by cardioversion after ≥7 days(8)) 

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- 
Previous pulmonary vein isolation 
- 
Cognitive or psychiatric condition 
- 
Diabetes mellitus 
- 
Ischemic heart disease 
- 
Heart failure 
- 
Asthma 
- 
Pregnancy 
- 
Previous/current drug or alcohol abuse 
- 
Previous neurological or concomitant musculoskeletal disorders 
- 
Continuous analgesic medication 
 
Patient consent and inclusion 
All potential patients will receive written information about the study and at the standard 
physician visit the day before the AF ablation, be asked to participate in the study. After 
obtaining written informed consent, patients will be asked to complete the Atrial fibrillation 
6 questionnaire (AF6) and the Short form 36 health survey (SF-36) questionnaires before a 
12-lead ECG is obtained. Comorbidities, medications and duration of AF will be documented 
and a routine clinical examination will be performed, and the modified European Heart 
Rhythm Association symptoms scale assessed. 
Blood samples 
Blood samples for biomarkers and epigenetic markers associated with pain, cardiac 
biomarkers, and inflammatory markers, will be obtained when standard blood samples are 
taken the day before the ablation, and the day after ablation. In total 30 ml of blood per 
time will be obtained. In controls, the same blood samples will be obtained once only. Blood 

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samples will be stored in a biobank for possible later analysis. Blood samples may be 
analysed in another laboratory in Sweden or in the EU/ESS. 
AF severity assessment 
The patient-reported AF6 questionnaire includes six items (breathing difficulties at rest and 
upon exertion, limitations in day-to-day life, feeling of discomfort, tiredness and 
worry/anxiety due to AF) and a score of 0 (no symptoms) to 10 (severe symptoms) is 
reported for each item, and all scores are added into a single sum score. Sum scores range 
from 0 to 60, with higher values reflecting more severe AF-related symptoms. The AF6 
includes a recall period of the last 7 days(32, 33). 
The physician-assessed modified European Heart Rhythm Association symptoms scale is 
used for symptom severity assessment in patients with AF, relating specifically to the time 
when patients feel symptoms of AF. Patients in class I are considered to have no symptoms, 
in class IIa mild, class IIb moderate, class III severe and in class IV disabling symptoms of 
AF(8, 34). 
 
Health-related quality of life 
The patient-reported SF-36 has a recall period of four weeks and consists of 36 items 
assessing eight domains ranging from 0 to 100, with higher values indicating better health-
related quality of life. The eight domains generate two summary measures: the physical 
component summary and the mental component summary scores, which will be used to 
assess health-related quality of life(35). 
 
Control group 

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Sex and age-matched controls will be recruited by advertisement. The same blood samples 
will be obtained from controls as on patients with AF but only once, and controls will be 
asked to complete the SF-36 questionnaire and a questionnaire about previous and current 
diseases and current medication. 
 
Follow-up 
No follow-up visits are scheduled. 
 
Primary endpoint 
The primary objectives are (1) to study the association of biomarkers and epigenetic markers 
and the severity of AF symptoms, and (2) to assess differences in the levels of biomarkers 
and epigenetic markers in patients with symptomatic AF compared with participants without 
AF.  
 
Secondary endpoint 
Secondary objectives are to study the association of age, sex, AF duration, health-related 
quality of life, and biomarkers and epigenetic markers.  
 
Ethics approval 
The study protocol is submitted to the Swedish Ethical Review Authority for approval. 
 
Statistics and data management 
Data collected during the study will be coded. 

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Statistical analysis 
Data will be presented as mean and standard deviation. Independent t-test will be used to 
compare biomarkers and epigenetic markers in AF patients and control subjects. Pearson 
correlations will be used for linear estimates and Spearman´s correlations for non-linear 
parameters. Multiple linear regression analysis will be performed to show associations 
between explanatory variables (age, sex, symptoms) and biomarkers and epigenetic markers 
associated with pain. Analyses will be performed using IBM SPSS Statistics 22 (Armonk, NY, 
USA) or STATA release 14 (College Station, TX, USA). 
 
Database and Case report form 
A case report form will be filled out and coded for each patient. The investigators are 
responsible for ensuring the accuracy, completeness, legibility and timeliness of the data 
recorded in the case report forms. 
Documentation and data collection 
Criteria for inclusion, informed consent, the decision to include the subject and the subject 
number will be documented in the subject’s hospital record.  
Insurance 
The subjects in the study are covered by the Swedish patient insurances. 
Economy 
The trial is an academic study conceived and conducted by healthcare personnel. The study 
is independent of commercial interests. Study logistics, handling of data and statistical 
assessment will be financed by the Department of Cardiology, Örebro University Hospital, 
Sweden. The investigators will apply for grants from public funds. Neither patients nor 
controls will receive economic compensation. 

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Ethical considerations 
The study will be conducted in accordance with the Declaration of Helsinki. The protocol is 
submitted to the Swedish Ethical Review Authority and the study will be initiated when the 
protocol has been approved. There are no known risks or complications associated with 
additional blood samples in association with standard blood samples being obtained, but it 
may cause some temporary discomfort. 
Risks, side effects, advantages and disadvantages in participation 
Subjects will be treated according to standard clinical practice. We do not expect that 
subjects will have any advantages or disadvantages from participating in the study. 
Guidelines for obtaining informed consent 
Subjects will enter the study after signing the informed consent form. Candidate participants 
will receive written information of the study, and oral information by a physician 
participating in the study. The subjects will be given time to think through participation in 
the study and to ask questions. Informed consent will be obtained by a Good Clinical Practice 
qualified physician participating in the study. 
Withdrawal 
A subject can withdraw from the study at any time. Data collected up to the end of follow-up 
will be used in the final analysis of the study. 
 
Publication 
Results, positive as well as negative or inconclusive, will be published in an international 
medical journal. 
 

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End of trial and archiving 
The study will end when the last subject has signed informed consent, completed the 
questionnaires and has undergone clinical examination and had blood samples taken. The 
steering committee reserves the right to terminate the study prematurely e.g. if the study 
participant recruitment is too slow, if study participant retention in the study is insufficient. 
Data collected during the study will be archived for at least 10 years after the study has been 
completed. 
 
 
 
 

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