Physiological and psychological factors in symptomatic atrial fibrillation
Authors: Skúladóttir Helga 
Published: November 2024

<p dir="ltr"><b>Introduction and overall aims</b></p><p dir="ltr">Atrial fibrillation (AF) is the most common clinical cardiac arrhythmia, with an estimated prevalence of 2-4% in the adult population. AF is associated with an increased risk of mortality and stroke and substantial costs, which can also relate to AF symptoms such as palpitations, shortness of breath, fatigue, and anxiety that affect healthcare-seeking patterns.</p><p dir="ltr">An intriguing observation is that some AF patients are asymptomatic, while others report debilitating symptoms despite a low AF burden. The factors that influence symptoms in AF can be divided into physiological and psychological factors, some of which are not fully understood. Psychological factors such as symptom preoccupation, manifesting as fear and hypervigilance toward cardiac-related symptoms, and avoidance behavior might play a pivotal role in AF symptomatology.</p><p dir="ltr">This thesis aimed to improve our understanding of symptomatic AF by studying the association of physiological and psychological factors with symptoms and AF- specific quality of life (QoL). A significant part of this work pertains to a novel psychological intervention that targets symptom preoccupation in paroxysmal AF.</p><p dir="ltr"><b>Methods and Results</b></p><p dir="ltr"><b>Study I </b>evaluated changes in physiological parameters and symptoms after electrical cardioversion (ECV) and assessed their correlation. We studied 44 patients (age 66.2+7.9 years, 84% males) before and 5+2 days after ECV when 28 (64%) were still in sinus rhythm (SR). In these patients, cardiac output (CO), as measured by non-invasive inert gas rebreathing, increased (0.8+0.7 L/min) as compared to those with recurrent AF (p<0.001). CO correlated with changes in Atrial fibrillation effect on the quality of life (AFEQT, r=0.36; p<0.05), AFEQT symptoms sub-score (r=0.46; p<0.01), Symptom Severity and Frequency (r=0.33; p<0.05 and r=0.62; p<0.01, respectively) and the modified European Heart Rhythm Associate (mEHRA) score (r=0.50; p<0.01). Decreased RR variability showed similar correlations with these symptom measures.</p><p dir="ltr"><b>Study II</b> is a pilot study where we devised an AF-specific cognitive behavioral therapy (AF-CBT) in collaboration with a team of psychologists and tested its feasibility in an uncontrolled study. Nineteen patients with symptomatic paroxysmal AF and troubling symptoms (i.e. EHRA class > 2b) were referred from local cardiology clinics. All patients completed the 10-week therapist-led intervention. We observed a significant improvement in AFEQT from 56.9+19.6 at baseline to 82.0+10.7 and 75.7+17.2 at post and six-month follow-up, respectively (p<0.001).</p><p dir="ltr"><b>Study III&IV</b></p><p dir="ltr">Studies III and IV are secondary studies to a randomized controlled trial that aimed to test the effect of a therapist-led, online AF-CBT on Qol in patients with paroxysmal symptomatic AF. We recruited patients from local cardiology clinics and nationwide by self-referral. The study included 127 patients (65.4+8.3 years, 58% women) who were randomized to a 10-week therapist-led online AF-CBT (n=65) or AF education (n=62). All participants underwent a thorough cardiological assessment to ensure they were on optimal medical therapy, excluding patients with an ejection fraction ≤35%. AFEQT increased from 62.4+14.3 to 83.7+ 13.8 points at the three-month follow-up (primary endpoint), with a relative difference of 15.0 points (p<0.001). Cardiac anxiety was also reduced from clinical to subclinical levels.</p><p dir="ltr"><b>Study III</b></p><p dir="ltr">AF-CBT exposes patients to avoided activities, including physical exercise, and although sleep is not targeted, it is related to anxiety and well-being. Heart rate variability (HRV) is linked to many behavioral risk factors for AF and anxiety. Thus, this study assessed the effects of AF-CBT on HRV, physical activity, and sleep.</p><p dir="ltr">A 5-day Patch-Holter with an integrated accelerometer was applied at baseline, post-treatment, and three-month follow-up. Physical activity and sleep duration did not change from baseline (8040+2600 steps/day and 8.0+1.1 hours of sleep), with no significant difference between the groups. Subjective insomnia, however, went from subclinical to near normal values, which was significant compared to controls (p=0.032). No significant changes were found in AF burden, HR, or HRV indices.</p><p dir="ltr"><b>Study IV</b></p><p dir="ltr">In this study, we assessed the short-term cost-effectiveness of AF-CBT from a societal perspective. Direct and indirect costs were assessed using a self-report questionnaire at baseline and three months after treatment and extrapolated to six months. A relative incremental cost-effectiveness ratio (ICER) was calculated for each point improvement on the AFEQT and per case of significant clinical improvement (defined as an increase of >5 AFEQT points). The intervention had a 97.3% probability of being cost-saving. The number needed to treat to achieve a significant improvement (>5 AFEQT points) compared to the control group was 2.5, and societal savings over six months for each case of clinically significant improvement was $6219.</p><p dir="ltr"><b>Conclusions</b>. Symptom improvement after ECV correlated with physiological parameters, most notably CO. In a pilot study, the novel psychological intervention, AF-CBT, demonstrated potential efficacy and feasibility in reducing symptoms and increasing Qol in AF patients. This was later corroborated in an RCT, which showed substantial AF-specific Qol improvements by AF-CBT.</p><p dir="ltr">However, this was achieved without affecting the AF burden, physical activity, sleep duration, or HRV, suggesting that the improvements are mediated by psychological and behavioral factors not targeted by current treatment modalities. Furthermore, AF-CBT appeared to be a cost-effective intervention from a societal perspective in the RCT setting.</p><p dir="ltr">AF-CBT might thus complement established medical treatments, including rhythm-controlling therapies and lifestyle interventions, within an integrated AF management approach. However, it must be tested in different populations and healthcare settings over an extended follow-up.</p><h3>List of scientific papers</h3><p dir="ltr">I. Klavebäck S, <b>Skúladóttir H,</b> Olbers J, Östergren J, Braunschweig F. Changes in cardiac output, rhythm regularity, and symptom severity after electrical cardioversion of atrial fibrillation. Scand Cardiovasc J. 2023;57(1):2236341. <a href="https://doi.org/10.1080/14017431.2023.2236341" rel="noreferrer" target="_blank">https://doi.org/10.1080/14017431.2023.2236341</a></p><p dir="ltr">II. Särnholm*J, Skúladóttir*H, Rück C, Pedersen S, Braunschweig F, Ljótsson B. *Equal contributors. Exposure-Based Therapy for Symptom Preoccupation in Atrial Fibrillation: An Uncontrolled Pilot Study. Behav Ther. 2017;48(6):808-819. <a href="https://doi.org/10.1016/j.beth.2017.06.001" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.beth.2017.06.001</a></p><p dir="ltr">III. <b>Skúladóttir H,</b> Särnholm J, Ólafsdóttir E, Arnardóttir ES, Hoppe K, Bottai M, Ljótsson B, Braunchweig F. Cognitive Behavioral Therapy for Paroxysmal Atrial Fibrillation: Heart Rate Variability, Physical Activity and Sleep. JACC Adv. 2024;3(11):101289. <a href="https://doi.org/10.1016/j.jacadv.2024.101289" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.jacadv.2024.101289</a></p><p dir="ltr">IV. <b>Skúladóttir H,</b> Särnholm J, Wallén H, Ólafsdóttir E, Ólafsson G, Braunchweig F, Ljótsson B. Cost-effectiveness of internet-based cognitive behavioral therapy for symptomatic paroxysmal atrial fibrillation. [Manuscript]</p>