Introduction Several studies have found celiac disease may be associated with a variety of cardiac manifestations. Atrial fibrillation (AF) is one of the most common arrhythmias that can cause significant morbidity. However, the risk of atrial fibrillation in patients with celiac disease according to epidemiological studies remains unclear. The aim of this meta-analysis study is to assess the risk of atrial fibrillation in patients diagnosed with celiac disease compared to controls. Methods A systematic literature review was conducted in MEDLINE, EMBASE, Cochrane databases from inception through December 2017 to identify studies that evaluated the risk of atrial fibrillation in patients with celiac disease. We included randomized controlled trial, cross sectional and cohort studies that reported the odds ratio, relative risk, hazard ratio, and standardized incidence ratio comparing the risk of developing atrial fibrillation among patients with celiac disease, versus patients without celiac disease as control. The Newcastle-Ottawa scale was used to determine the quality of the studies. Effect estimates from individual studies were extracted and combined using random-effect, generic inverse variance method of DerSimonian and Laird. Results Celiac disease is an autoimmune condition. This inflammatory state predisposes patients to develop AF. After a review of the literature, four observational studies with a total of 64,397 participants were enrolled. The association between celiac disease and increased risk of atrial fibrillation was significant, with a pooled OR of 1.38 (95% CI: 1.01-1.88). No publication bias as assessed by the funnel plots and Egger's regression asymmetry test with p = 0.54. However, the heterogeneity of the included studies was high (I2 = 96). Conclusion A significant association between celiac disease and risk of atrial fibrillation was reported in this study. There is a 38% increased risk of atrial fibrillation. Additional studies are needed to clarify the mechanistic link between atrial fibrillation and celiac disease. Some of the limitations of this study are that all were observational studies, some were medical registry-based and there was high heterogeneity between studies.

Stroke is an acute neurological deficit that results from abnormal blood flow to the brain. The term stroke encompasses two primary subgroups: hemorrhagic stroke that is due to extravasation of blood and ischemic stroke that is due to vessel obstruction. Determining stroke type and underlying etiology is a crucial step in patient management as it influences treatment strategies. Currently diagnosis of stroke relies on clinical examination and neuroimaging, but there is a lack of rapid diagnostic and prognostic testing. Using microarray technology we identified a novel association between elevated peripheral blood expression of MCEMP1 and stroke. We have also shown that MCEMP1 discriminates between primary stroke types and predicts one-month post-stroke prognosis. Since genetic mechanisms underlying stroke remain incompletely understood we next conducted a global gene network analysis. Network analysis identified four large groups of co-expressed genes associated with ischemic stroke. NLRC4, CKLF, and HS.546375 were the most interconnected genes within unique modules and each was also independently associated with ischemic stroke. We show that multi-gene models have greater discriminative capacity for stroke and stroke prognosis, than single gene models. In addition to stroke biomarkers we also identified biomarkers of atrial fibrillation (AF), a known risk factor of stroke. Currently our understanding of the molecular mechanisms underlying AF remains incompletely understood. Thus we conducted whole blood expression profiling in patients with persistent AF before and after successful electrical cardioversion, a procedure that aims to restore sinus rhythm to the heart. We identified elevated expression of SLC25A20 and PDK4 during AF as compared with sinus rhythm. Furthermore we show that SLC25A20, PDK4 and NT-proBNP have incremental utility to discriminate AF from sinus rhythm. Taken together, the thesis implicates new genes with stroke and AF, and also indicates that whole blood RNA biomarkers may have clinical utility. / Thesis / Doctor of Philosophy (PhD)

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with a poor cardiovascular disease risk profile, dramatically reduced quality of life (QoL), and a high risk of mortality. In 2020, the Canadian Cardiovascular Society (CCS) released the first exercise targets (≥200 minutes/week of moderate intensity physical activity (PA), 2-3 days/week of resistance training, and if >65 years of age, 10 minutes/day of flexibility exercise 2 days/week) for patients with AF and included exercise physiology in an integrated care model for those living with AF. Inclusion of exercise targets and exercise physiology in the guidelines may influence the PA recommendations provided by healthcare providers (HCP) and patient PA levels for people with AF. The overall purpose of this thesis was to explore the implementation of the exercise recommendations within the 2020 CCS AF guidelines. Study 1 was an observational study aimed at determining if HCPs of patients with AF are discussing PA and exercise with their patients using a self-report questionnaire and physician reports from patient medical charts. The secondary purposes were to explore potential differences in PA and exercise discussion occurrence and prescription, and whether this information is different based on patients’ PA levels and sex. Of the 195 patients, 49% reported not discussing PA or exercise with their University of Ottawa Heart Institute (UOHI) physician. Of the patients who reported a PA and exercise discussion with a UOHI physician, 23% did not have a record of the discussion in their medical charts. Significantly more patients discussed PA and exercise with both their UOHI and family physicians than either of these providers alone (𝛘²=21.64, p<0.001). The occurrence of a PA and exercise discussion was not associated with patients' measured PA levels. Females were provided frequency prescription (i.e., how often to exercise) more than males (𝛘²=3.97, p=0.046), but no other sex differences were identified. Study 2 was a pan-Canadian observational study which used a HCP self-report survey to determine: (i) if HCPs prescribe PA and exercise for patients with AF; (ii) if HCPs believed exercise physiology should be included in AF management; (iii) which HCPs have the highest confidence in prescribing exercise; (iv) which HCPs have exercise prescription training; and (v) if HCPs know the 2020 CCS AF exercise targets. Of the 96 responses, 87% of HCPs reported prescribing PA to their patients with AF at least some of the time. All HCPs believed exercise physiology should be included in AF management. Physicians (60%), kinesiologists (50%), and exercise physiologists (40%) reported always prescribing exercise to patients with AF, which was significantly more than registered nurses (0%; 𝛘²=37.37, p<0.05). More physicians (80%) reported being fairly confident in prescribing exercise to patients with AF than physiotherapists (7%) and registered nurses (6%; 𝛘²=43.14, all p<0.05). More exercise physiologists (95%), kinesiologists (90%), and physiotherapists (78.6%) reported being trained in exercise prescription than registered nurses (11.8%; 𝛘²=23.57, all p<0.05). Only 22.9% of HCPs knew the AF targets were from the CCS, and only 14.6% of HCPs correctly identified all three exercise targets from CCS. Conclusion: This thesis suggests that most HCPs are discussing or prescribing exercise to patients with AF, and that exercise physiologists, kinesiologists, and physicians were the healthcare providers most likely to prescribe exercise to their patients. Future research should focus on progressing toward an AF specific PA counseling method and disseminating the CCS AF guidelines to HCPs of patients with AF, based on the lack of identification of the 2020 CCS AF exercise targets and confidence in prescribing to patients who have AF.

Despite decades of research and thousands of studies on cardiac electrophysiology, cardiovascular disease remains among the leading causes of death in the United States today. Despite substantially beneficial advances, we have largely shifted cardiovascular disease from an acute to a chronic issue. It is therefore clear that our current understanding of the heart's functions remain inadequate and we must search for untapped therapeutic approaches to eliminate these deadly and costly ailments once and for all. This thesis will focus on the electrophysiology of the heart, specifically the mechanisms of cell-to-cell conduction. Canonically, the understood mechanism of cardiac conduction is through gap junctions (GJ) following a cable-like conduction model. While both experimentally and mathematically, this understanding of conduction has explained cardiac electrical behavior, it is also incomplete, as evidenced by recent conflicting modeling and experimental data. The overall goal of this thesis is to explore a structure modulating an ephaptic, or electric field, cellular coupling mechanism: the GJ-adjacent perinexus, with three specific aims. First, I identified the perinexus – a recently-established structure in rodent myocardium – in human atrial tissue. I also observed a significant tendency for open-heart surgery patients with pre-operative atrial fibrillation to have wider perinexi, indicating a possibly targetable mechanism of atrial fibrillation, one of the costliest, and most poorly-understood cardiac diseases. Next, I developed a high-throughput, high-resolution method for quantifying the perinexus. Finally, I sought to reconcile a major controversy in the field: whether cardiac edema could either be beneficial or harmful to cardiac conduction. Using a Langendorff perfusion model, I added osmotic agents of various sizes to guinea pig hearts and measured electrical and structural parameters. My findings suggest that while cardiac conduction is multifaceted and influenced by several parameters, the strongest correlation is an inverse relationship between conduction velocity and the width of the perinexus. This study is the first to osmotically expand and narrow the perinexus and show an inverse correlation with conduction. Importantly, my conduction data cannot be explained by factors consistent with a cable-like conduction mechanism, indicating once again that the perinexus could be a therapeutic target for a myriad of cardiac conduction diseases. / Doctor of Philosophy / The ways by which cells in the heart communicate have been studied extensively and are thought to be well-understood. However, despite decades of research, cardiovascular disease is a major problem in the developed world today and we remain unable to develop treatments to truly cure many major cardiac diseases. Because of this lack of clinical success in preventing or treating conditions such as atrial fibrillation, Brugada syndrome and sudden cardiac death, all of which are associated with disruptions in the heart’s electrical communication systems, I have sought to better understand the ways by which cellular communication is achieved. Currently, we think of cardiac tissue to propagate electrical signals as if it was a series of cables, just like the electrical wires over our streets and in our homes. However, we have seen experimental evidence, along with computer simulations, that supports the idea of a second mechanism of cellular electrical conduction. This second mechanism is called ephaptic, or electric field, coupling and relies on changes in charges inside and outside the cell to trigger the action potential – the electrical signal which tells the cell to contract. In order for ephaptic coupling to occur, two main conditions must be met. First, there must be a suitably-sized cleft, or ephapse, between adjacent cells. Models have estimated this space to be between 10-100 nm wide. Second, there must be a large concentration of sodium channels, as sodium ions are primarily used to set off the action potential. The region in which I am most interested is the cardiac perinexus, which is the space immediately adjacent to plaques of connexin proteins which link adjacent cells. The perinexus is both of an appropriate size (we’ve measured it between 10 and 25 nm on average) and rich in sodium channels, making it an ideal candidate to be a cardiac ephapse. In recent years, our lab has shown experimentally that expanding this space can disrupt cardiac conduction and my first study showed that clinically, patients with chronic atrial fibrillation (a-fib) prior to open-heart surgery have wider perinexi than patients without chronic a-fib. No one, however, has been able to demonstrate that narrowing the perinexus would be therapeutic by making it easier for cells to communicate via this ephaptic mechanism. Knowing I would need a better method for measuring the width of huge numbers of perinexi, I then developed a faster, more precise measurement program. Finally, I perfused several osmotic agents – substances which would theoretically draw fluid into or out of various compartments of cardiac tissue – into guinea pig hearts and observed changes to both their electrical behavior and tissue structure. Using my new perinexal measurement program, I found that changing the perinexus was the only factor that could explain the conduction changes I observed with each osmotic agent and that parameters associated with cable theory, such as gap junctional protein expression or interstitial resistance, could not explain conduction changes. Therefore, I have indicated, along with my clinical study, that the cardiac perinexus could be a therapeutic target for preventing, managing, or possibly even curing cardiac conduction diseases.

Vorhofflimmern (VHF) ist eine progressive Krankheit, die sich morphologisch als fibrotische Remodellierung des Vorhofs manifestiert und klinisch durch einen Wechsel von paroxysmalem zu persistierendem VHF, eine Vergrößerung des links-atrialen Diameters und die intra-prozedurale Detektion von atrialen Bereichen mit niedrigen Potentialen gekennzeichnet ist. VHF-Progression ist mit schlechteren Therapieergebnissen, z.B. einer höheren VHF-Rezidivrate assoziiert. Zugrunde liegende Pathomechanismen sind unvollständig charakterisiert, geeignete Biomarker zur individuellen therapeutischen Stratifizierung sind nicht bekannt. Die Mehrzahl häufiger genetischer Varianten, die mit der VHF-Progression assoziiert sind, hat nur sehr kleine Effekte. Viele Varianten könnten hingegen additiv die Progression von VHF modulieren. Dieser Hypothese folgend wurden mit VHF-Progression assoziierte Varianten identifiziert und deren nicht-zufällige Häufung in Gen-Loci als Indiz für eine kontextuelle Relevanz des jeweiligen Gens gewertet. Die identifizierten Gene wurden der Kalzium-Signaltransduktion und der extrazelluläre Matrix (ECM)-Rezeptor-Interaktion zugeordnet. Zusätzlich wurden die zentralen Regulatoren dieser Signalwege, namentlich EGFR, RYR2, PRKCA, FN1 und LAMA1 identifiziert, die als pharmakologische Ziele in Frage kommen bzw. hinsichtlich ihrer Rolle bei der VHF-Progression untersucht werden müssen. Mit einer vergleichbaren Herangehensweise wurde gezeigt, dass die mit der Manifestation von VHF assoziierten Gene ZFHX3, ITGA9 und SOX5 auch mit der VHF-Progression assoziiert sind. Eine Analyse potentieller Biomarker identifizierte NT-pro ANP als spezifischen Marker mit direkter Korrelation zum Progressionsgrad des VHF. Zusätzlich wurde für die Marker NT-proANP, NT-proBNP und VCAM1 ein stufenweise signifikanter Anstieg korrelierend mit einem klinischen Wert zur Prognose von VHF-Rezidiven gezeigt. Durch die Anwendung unkonventioneller Konzepte und der Verwendung spezifischer Charakteristika der VHF-Progression konnten in der vorliegenden Arbeit potentielle Regulatoren und Biomarker der VHF-Progression identifiziert werden.:1. Introduction 5 1.1. Atrial fibrillation incidence and associated risk 5 1.2. Atrial fibrillation therapy and recurrence 6 1.3. Atrial fibrillation progression phenotypes 7 1.3.1. Atrial fibrillation type 7 1.3.2. Left atrial diameter 8 1.3.3. Low voltage areas 8 1.3.4. PR interval 8 1.4. Pathomechanisms of atrial fibrillation progression 9 1.4.1. Electrical remodeling 9 1.4.2. Structural remodeling and fibrosis 10 1.4.3. Autonomic remodeling 11 1.5. Genetic background of atrial fibrillation 11 1.5.1. Heritable atrial fibrillation and the impact of rare variants 12 1.5.2. Genetic predisposition and the impact of common variants 12 1.5.3. New concepts for GWAS analysis of genetic background 13 1.6. Personalized medicine 15 1.6.1. Clinical scores for risk prediction in atrial fibrillation 15 1.6.2. Clinical scores for prediction of AF progression and recurrence 15 1.6.3. New concepts in personalized medicine 16 1.7.1. Schematic overview on AF progression and associated open questions 16 2. Hypotheses 18 3. Publications 19 3.1. New concepts on genetic background of AF progression and recurrence 19 3.1.1. Genomic contributors to atrial electroanatomical remodeling and atrial fibrillation progression: Pathway enrichment analysis of GWAS data. (Publication 1) 20 3.1.2. Genomic Contributors to Rhythm Outcome of Atrial Fibrillation Catheter Ablation - Pathway Enrichment Analysis of GWAS Data. (Publication 2) 28 3.1.3. Identification of Central Regulators of Calcium Signaling and ECM-Receptor Interaction Genetically Associated With the Progression and Recurrence of Atrial Fibrillation. (Publication 3) 40 3.1.4. Association of atrial fibrillation susceptibility genes, atrial fibrillation phenotypes and response to catheter ablation: a gene-based analysis of GWAS data. (Publication 4) 47 3.1.5. PR Interval Associated Genes, Atrial Remodeling and Rhythm Outcome of Catheter Ablation of Atrial Fibrillation—A Gene-Based Analysis of GWAS Data. (Publication 5) 54 3.2. New concepts on biomarkers of AF progression and recurrence 3.2.1. Role of NT-proANP and NT-proBNP in patients with atrial fibrillation: Association with atrial fibrillation progression phenotypes. (Publication 6) 61 3.2.2. Prediction of electro-anatomical substrate using APPLE score and biomarkers. (Publication 7) 68 4. Conclusions 75 5. References 76 6. Abbreviations 86 7. Erklärungen zur vorgelegten Habilitationsschrift 87 8. Lebenslauf 88 9. Danksagung 91

Objective: A systematic review and meta-analysis was performed to evaluate the safety and efficacy of drug-eluting stents (DES) vs bare-metal stents (BMS) in atrial fibrillation (AF) patients. Methods: We systematically searched 5 engines until May 2019 for cohort studies and randomized controlled trials (RCTs). Primary outcomes were major bleeding and major adverse cardiac events (MACE) including cardiac death, myocardial infarction, target vessel revascularization (TVR) or stent thrombosis. Effects of inverse variance random meta-analyses were described with relative risks (RR) and their 95% confidence intervals (CI). We also stratified analyses by type (triple [TAT] vs dual [DAT]) and duration (short-vs long-term) of antithrombotic therapy. Results: Ten studies (3 RCTs; 7 cohorts) including 10,353 patients (DES: 59.6%) were identified. DES did not show higher risk of major bleeding than BMS (5.6% vs 6.9%, RR 1.07; 95%CI, 0.89–1.28, p = 0.47; I2 = 0%) or MACE (12% vs 13.6%; RR 0.96; 95%CI 0.81–1.13, p = 0.60; I2 = 44%). Although, DES almost decreased TVR risk (6.4% vs 8.4%, RR 0.78; 95%CI, 0.61–1.01, p = 0.06; I2 = 15%). Stratified analyses by type and duration of antithrombotic therapy showed no differences in major bleeding or MACE between both types of stents. In DES, long-term TAT showed higher major bleeding risk than long-term DAT (7.7% vs 4.7%, RR 1.48, 95%CI 1.08–2.03, p = 0.01; I2 = 12%). For both types of stents, MACE risk was similar between TAT and DAT. Conclusions: In patients with AF undergoing PCI, DES had similar rate of major bleeding and MACE than BMS. DAT seems to be a safer antithrombotic therapy compared with TAT. / Janssen Pharmaceuticals / Revisión por pares

No description available.

Roughly thirty percent of coronary artery bypass graft (CABG) patients develop atrial fibrillation (AF) in the five days following surgery, increasing the risk of stroke, prolonging hospital stay three to four days, and increasing the overall cost of the procedure. Current pharmacologic and nonpharmacologic means of AF prevention are suboptimal, and their side effects, expense, and inconvenience limit their widespread application. An accurate method for identifying patients at high risk for postoperative AF would allow these methods to be focused on the patients on which its utility would be highest. The main objective of this research was to develop a Bayesian network (BN) which could model/predict/assign risk of the occurrence of atrial fibrillation in CABG patients using retrospective data. A secondary objective was to develop an integrated framework for more advanced methods of feature selection and fusion for medical classification/prediction. We determined that the naïve Bayesian network classifier used with features selected by a genetic algorithm is a better classifier to use, given our cohort. The naïve BN allows for reasonable prediction despite being presented with patients with missing data points as might occur in the hospital. This classifier achieves a sensitivity of 0.63 and a specificity of 0.73 with an AUC of 0.74. Furthermore, this system is based on probabilities that are well understood and easily incorporated into a clinical environment. These probabilities can be altered based on the cardiologists prior knowledge through Bayesian statistics, allowing for online sensitivity analysis by doctors, to perceive the best treatment options. Contributions of this research include: - An accurate, physician-friendly, postoperative AF risk stratification system that performs even under missing data conditions, while outperforming the state of the art system, - A thorough analysis of previously examined and novel pre- and postoperative clinical and ECG features for postoperative AF risk stratification, - A new methodology for genetic algorithm-built traditional Bayesian network classifiers allowing dynamic structure through novel chromosome, operator, and fitness definitions, and - An integrated methodology for inclusion of doctor s expert knowledge into a probabilistic diagnosis support system.

This thesis focuses on the issue of atrial fibrillation and the success of their detection in the ECG signal. It provides a description of electrical activity of the heart with the theoretical analysis of atrial fibrillation and methods for their detection. Additionally the work describes procedures for the implementation of three selected methods for the detection of atrial fibrillation in the MATLAB environment, presents the results of their tests on two atrial fibrillation signal databases and assesses the accuracy of each method.

Objective: The primary objective of this study was to estimate the long-term cost-effectiveness of stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) in the United States using new anticoagulant therapies - dabigatran 150 mg, apixaban 5 mg, and rivaroxaban 20 mg - as well as the standard treatment, warfarin. Methods: A Markov decision-analysis model was constructed using data from clinical trials that evaluated the new oral anticoagulants relative to warfarin (apixaban 5 mg & ARISTOTLE, dabigatran 150 mg & RE-LY, and rivaroxaban 20 mg & ROCKET-AF) to compare the lifetime cost and quality-adjusted life expectancy. The Markov model target population was a hypothetical cohort of 70-year old patients with nonvalvular atrial fibrillation, an increased risk for stroke (CHADS₂ ≥ 1, or equivalent), a renal creatinine clearance (CrCl) of 50 or above, and no contraindication to anticoagulant therapy. Using pair-wise comparisons of each therapy, analyses were conducted to evaluate incremental cost-effectiveness ratios (ICERs), net monetary benefits (NMBs), lifetime costs, life-years, and quality-adjusted life-years (QALYs). Results: In the base case, warfarin had the lowest cost of $71,857 (95% confidence interval [CI]: $68,730, $77,452), followed by rivaroxaban 20 mg ($74,023; 95% CI: $70,943, $77,307), dabigatran 150 mg ($78,584; 95% CI: $75,277, $81,968), and apixaban 5 mg ($81,180; 95% CI: $78,642, $83,756). Apixaban 5 mg also yielded the highest QALY estimate, 8.63 (95% CI: 8.52, 8.72), followed by dabigatran 150 mg (8.55; 95% CI: 8.43, 8.67), rivaroxaban 20 mg (8.42; 95% CI: 8.31, 8.54), and warfarin (8.17; 95% CI: 8.1, 8.24). In a Monte Carlo probabilistic sensitivity analysis, apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg, and warfarin were cost effective in 45%, 37%, 19%, 0%, respectively, of the simulations using a willingness-to pay threshold of $50,000 per QALY gained. From the one-way sensitivity analyses, new anticoagulant (apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg) costs and probabilities associated with intracranial hemorrhage and stroke for patients receiving rivaroxaban 20 mg were identified as significant influential variables impacting model results. Conclusion: In patients with NVAF and an increased risk of stroke prophylaxis, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg may all be cost-effective alternatives to warfarin depending on pricing in the United States and neurologic events for rivaroxaban 20 mg.