Methods
Study population
Study participants were recruited from a database consisting of all individuals aged 20 years or older with an initial or recurrent AF diagnosis between 1 January 2015 and 31 December 2018 in Örebro County, Sweden. The database comprised patients derived from the Medrave 4 Registry for primary care, the Auricula Registry (national quality registry for anticoagulation treatment) and the National Patient Registry for inpatient and specialised outpatient care. Eligibility criteria for the current study were ≤75 years old, permanent AF (persistent AF for which no further attempts to restore sinus rhythm will be undertaken10) and a previously completed AF6 questionnaire11 in spring of 2021. Reasons for exclusion were pregnancy, diabetes mellitus, previous AF ablation, psychiatric condition or cognitive impairment, drug or alcohol abuse, previous or concomitant neurological musculoskeletal disorder or continuous analgesic medication. Candidate participants received written study information and were offered an outpatient visit to a physician (AB) at the Department of Cardiology, Örebro University Hospital. Patients were asked not to take analgesic medication within the 24 hours preceding the visit. After obtaining written informed consent, patients were asked to repeat the AF6 and SF-3612 questionnaires, rate their chest pain symptoms on the Visual Analogue Scale (VAS) and draw the area of pain on a body chart. Comorbidities, medications, duration of AF and ranking on the modified European Heart Rhythm Association (EHRA) symptom scale13 were documented, and a routine clinical examination was performed including a 12-lead ECG. All data were obtained during the visit and no follow-up visits were conducted. Subjects were divided into two groups based on their earlier AF6 sum scores: 15 asymptomatic patients with an AF6 sum score of 0, and 15 symptomatic patients with an AF6 sum score of ≥30. The cut-off of 30 was based on a study showing patients scheduled for AF ablation, who are generally highly symptomatic, to have a median score of 30 points.14 Sample size flat rules of thumb was used as this was a proof-of-concept study.15 The study was conducted in accordance with the Declaration of Helsinki.
Symptom assessment and health-related quality of life
The patient-reported AF6 questionnaire has a recall period of 7 days and includes breathing difficulties at rest, breathing difficulties on exertion, limitations in day-to-day life, feeling of discomfort, tiredness and worry and/or anxiety due to AF. A score of 0 (no symptoms) to 10 (severe symptoms) is reported for each of the six items and scores are added to obtain a cumulative sum score ranging from 0 to 60, with higher values reflecting more severe symptoms.11 16
The physician-assessed modified EHRA scale was used to assess symptom severity relating specifically to the time when patients feel symptoms of AF. Patients reporting no AF symptoms are categorised as class I. Class IIa experienced mild, class IIb moderate, class III severe and class IV, disabling symptoms.13
The patient-reported SF-36 has a recall period of 4 weeks and consists of 36 items assessing eight domains on a scale ranging from 0 to 100, with higher values indicating better health-related quality of life. The eight domains generate a physical component summary score and a mental component summary score, which were used to assess health-related quality of life.12
Quantitative sensory testing
Quantitative sensory tests were conducted by a blinded investigator (AJ) in the following order: pressure pain threshold (PPT), temporal summation of pain (TSP) and conditioned pain modulation (CPM). PPTs and TSP were performed at the tibialis anterior muscle 5 cm distal to the tibial tuberosity, and at the sternum between the third and fifth intercostal spaces, with 1 min intervals between repeats and sites.17 The sites were chosen to reflect localised (sternum, referred pain area) and generalised (tibialis anterior muscle) manifestations of sensitisation. Patients were free to stop the test at any time.
PPT
The PPT was defined as the minimum pressure required for the sensation of pressure to change to pain. The 1 cm2 probe of the handheld pressure algometer (Somedic AB, Sweden) was placed perpendicular to the skin, and pressure was increased at a rate of approximately 30 kPa/s. Participants were instructed to press the stop button on the algometer when they first experienced the sensation of pain. The mean of three measurements at each site was used for analysis.
TSP
A pin-prick device (0.25 mm2 tip) with a weighted load (Aalborg University, Denmark) was used to induce TSP.18 19 A force of 60 g was applied to both sites, and patients were asked to rate the pain intensity on a VAS (0 to 10). Ten consecutive stimuli were applied with a 1 s interval between stimuli and the subjects were asked to rate the pain intensity of the final stimulation on the VAS. Temporal summation of pain was defined as the difference in pain intensity between the first and the final stimulation. Higher TSP scores indicated facilitated temporal summation.
CPM
The right hand was immersed up to the wrist in circulating water at 2°C–4 °C for up to 2 min (cold pressor test). The PPT from both sites were assessed before (unconditioned) and after (conditioned) the 2 min immersion and reassessed 10 minutes after the hand was withdrawn from the water. The CPM was calculated as the absolute difference in PPT during the immersion compared with the pre-immersion PPT. A negative value indicates inefficient CPM and a positive value indicates efficient CPM.
Statistical analysis
Data were tested for normality using the Shapiro-Wilk’s test. Independent sample t-tests were performed to analyse differences between groups in age, BMI, AF duration and physical/mental component summary scores, and dependent sample t-tests to quantify difference in initial and repeat AF6 sum scores.
The χ2 test was employed to test for differences in sex, comorbidities, rate control agents (beta-blockers, verapamil, diltiazem and digoxin individually or combined), and completion of the full 2 min immersion cold pressor test between the two groups. A mixed model analysis of variance (ANOVA) was used to assess the primary objective of the study, with within-factor time (baseline, 2 min and 10 min), and between groups. One-way ANOVA was used to characterise differences in CPM and TSP. To adjust for age, sex and BMI, these variables were included as covariates for CPM and TSP. Sidak-corrected post hoc tests were employed where appropriate, if main or interaction factors were significant. Secondary objectives were tested using correlational analyses, Pearson’s product-moment or Spearman’s rank correlation where appropriate for demographic and clinical parameters, and pain sensitisation as reflected by PPT, CPM and TSP. A p<0.05 was considered significant. Data were reported as mean±SEM unless otherwise stated. Statistical analyses were performed using IBM SPSS Statistics V.27.
Patient and public involvement
Patients and public were not invited to comment on the study design and were not consulted to develop outcomes relevant to patients or to interpret the results. Patients were not invited to contribute to the writing or editing of this document for readability or accuracy. Before publication, the results of this study were not disseminated to patients or the public.