Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with high morbidity and mortality. Major improvements have been made in the diagnosis and management of AF in the past two decades. However, important questions pertaining to the screening, prognosis, risk stratification, and management of AF remain unanswered. This thesis presents original studies addressing knowledge gaps in these aspects of AF.
In Chapter 2, using a large cohort of individuals from the UK Biobank, we investigated the association between lung function and incident AF. We observed that reduced ventilatory function was associated with increased risk of AF independently of age, sex, smoking, and several other known AF risk factors. This suggests that individuals with substantial reduction of their lung function might represent an appropriate population for targeted AF screening and ventilatory parameters might improve AF risk prediction.
Chapter 3 assesses data related to implantable cardiac monitors (ICM). The first section reports AF diagnostic yield in a real-world cohort of patients receiving prolonged cardiac monitoring with ICM for stroke and unexplained syncope. It indicates that patients with stroke or transient ischemic attack (TIA) have a higher rate of AF detection compared with patients with unexplained syncope. However, this real-world study shows AF detection rates following stroke significantly lower than what has been previously reported. The second section of this chapter summarizes data on AF detection rates across different rhythm monitoring strategies (non-invasive and ICM) in patients with cryptogenic stroke (CS) or embolic stroke of undetermined source (ESUS). It shows that the yield of ICM increases with the duration of monitoring; more than a quarter of patients with CS or ESUS will be diagnosed with AF during follow-up. About one in seven patients have AF detected within a month of mobile cardiac outpatient telemetry, suggesting that a non-invasive rhythm monitoring strategy should be considered before invasive monitoring.
Chapters 4 and 5 address risk stratification in patients with AF. Chapter 4 has two sections. The first section is a meta-analysis that comprehensively summarizes data from prospective cohort studies on clinical predictors of stroke in anticoagulant-naïve patients with AF. It shows that although weighted similarly in most risk stratification schemes such as the CHA2DS2-VASc score, the absolute risk of stroke attributable to hypertension, diabetes, vascular disease, and heart failure may not be the same in individual patients. Furthermore, it shows that female sex seems not to be universally associated with stroke or systemic embolism, suggesting that the decision to initiate oral anticoagulation should not be made on the sole basis of female sex as currently recommended by some scientific societies. By compiling evidence from various studies, the second section of this chapter demonstrates that some anatomic and functional cardiac imaging parameters are associated with stroke in patients with AF and therefore, might improve stroke risk stratification in these patients. Chapter 5 presents two systematic reviews and meta-analysis which show that AF and carotid artery disease frequently co-exist, with about one in ten patients with AF who has carotid stenosis, and vice versa; and non-stenotic carotid disease being much more frequent. Moreover, there is an association between carotid atherosclerosis and the risk of stroke in patients with AF, suggesting that the incorporation of carotid atherosclerosis and characteristics of carotid plaques into scoring systems might improve stroke prediction in patients with AF. Taking this further, the last section of this chapter investigates the potential added value of high-risk carotid plaques on stroke risk stratification compared to the classical CHA₂DS₂-VASc score in a prospective cohort of patients with AF. It shows a low prevalence (5.5%) of moderate to severe carotid stenosis (≥ 50%), whereas one in three participants have carotid plaques considered vulnerable or high-risk. Neither the degree of carotid stenosis nor the presence of vulnerable plaques is associated with incident ischemic stroke, suggesting that carotid disease is probably not an important cause of ischemic stroke in this group of patients with AF and therefore, vulnerable carotid plaques might not improve stroke risk stratification in patients with AF.
Chapter 6 presents two pooled analyses of data on the prognostic impact of AF on acute coronary syndromes (ACS) and acute pulmonary embolism (aPE). The first section of the chapter shows that AF is common in patients with ACS (one in nine) and that it (especially newly diagnosed AF) is associated with poor short-term and long-term outcomes including re-infarction, heart failure, stroke, acute kidney injury, heart failure, major bleeding, and death. Likewise, the second section of the chapter demonstrates that AF is frequent in patients with aPE (one in eight) and is associated with increased short-term and long-term mortality. Considering this strong prognostic impact of AF in patients with ACS and aPE, its incorporation into risk stratification schemes for these patients should be considered. Furthermore, considering the significant incidence of AF in patients with ACS and aPE, studies are needed to determine the appropriate rhythm monitoring strategies in these patients.
Chapters 7-9 focus on sex differences in the management of AF. Chapter 7 analyses data from 142 randomized controlled trials (RCTs) of AF published in top tiers cardiovascular journals and shows that despite recent progress, females remain substantially less represented in RCTs of AF. This raises concern about the generalizability of these trials and the validity of the evidence guiding the treatment of females. Furthermore, primary outcomes are infrequently reported by sex in these RCTs of AF. Considering established benefit of risk factor modification on outcomes in patients with AF, Chapter 8 assesses sex differences in weight-loss, cardiorespiratory fitness gain, and progression and recurrence of AF in patients undergoing aggressive risk factor modification. It shows that despite sex differences in some baseline characteristics, the benefits of weight-loss and fitness gain were favourable for both males and females. However, improvement in fitness had a much greater benefit for total arrhythmia freedom for females, whereas there was a trend towards more common regression from persistent to paroxysmal AF in males. These findings reinforce the need to address lifestyle risk factors to minimize arrhythmia recurrence and reduce symptom severity for all individuals. Finally, Chapter 9 investigates the impact of sex on the clinical profile, utilization of rhythm control therapies, in-hospital mortality, length of stay (LOS), and cost of hospitalization in patients admitted for AF in the United States. It shows similarities and disparities in risk factors for mortality between males and females, and that unlike what has been reported in several previous studies, although women had a relatively higher mortality rate, after risk adjustment, female sex was not a predictor of mortality.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 02
