京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第20626号 / 社医博第84号 / 社新制||医||9(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 佐藤 俊哉, 教授 木村 剛, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

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ABSTRACT Atrial fibrillation (AF) is frequently detected in the setting of an acute physiologic stressor, such as medical illness or surgery. It is uncertain if AF detected in these settings (AFOTS: AF occurring transiently with stress) is secondary to a reversible trigger or is simply paroxysmal AF. This distinction is critical for clinicians and patients, as they must decide if AFOTS can be dismissed as a reversible phenomenon, or if it justifies the need for chronic therapy; in particular, anticoagulation to reduce the risk of disabling stroke. The uncertainty in the management of AFOTS is exacerbated by a poor understanding of its epidemiology. How frequently does AFOTS occur? Are there higher risk groups? What is the natural history of this condition? Across 8 chapters, this thesis systematically assesses previously published literature on this topic, focusing on patients who have an acute medical illness or have undergone noncardiac surgery, and addresses knowledge gaps therein. Chapter 1 is an introduction that outlines the justification of each of the studies in the thesis. Chapter 2 is a narrative review that defines AFOTS conceptually and outlines research priorities. Chapter 3 is a systematic review that explores the incidence and recurrence of AFOTS associated with acute medical illness. Chapter 4 is a systematic review and meta-analysis that explores the incidence and recurrence of AFOTS associated with acute noncardiac surgery. iii Chapter 5 examines the profiles of pacemaker-detected “subclinical” AF occurring before and after a hospitalization for medical illness or noncardiac surgery Chapter 6 reports the design, rationale and final results of a prospective study that aimed to provide a precise and accurate estimate of the incidence of AFOTS in critically ill patients. Chapter 7 reports the design and rationale of a matched prospective cohort study designed to estimate the rate of recurrence of AF following hospitalization with AFOTS and to compare it to similar patients who did not have AFOTS. Finally, Chapter 8 outlines the conclusions, discusses the limitations, and presents the implications of the research in this PhD thesis. / Thesis / Doctor of Philosophy (PhD) / Atrial fibrillation (AF) is the most common abnormal heart rhythm. AF is often diagnosed when a patient is hospitalized for an illness or after surgery. When AF is first found in this setting, it is unclear whether it has the same prognosis as other forms of the disease or is reversible. This thesis examines this problem and designs and executes studies to address it.

Almost half of patients recovering from open chest surgery experience atrial fibrillation (AF) that results principally from inflammation in the pericardial space surrounding the heart. Given that post-operative AF is associated with increased mortality, effective measures to prevent AF after open-chest surgery are highly desirable. In this study, we tested the concept that extracellular vesicles (EVs) isolated from human atrial explant-derived cells can prevent post-operative AF. Middle-aged female and male rats were randomized to undergo sham operation or induction of sterile pericarditis followed by trans-epicardial injection of human EVs or vehicle into the atrial tissue. Pericarditis increased the probability of inducing AF while EV treatment abrogated this effect in a sex independent manner. EV treatment reduced infiltration of inflammatory cells and production of pro-inflammatory cytokines. Atrial fibrosis and hypertrophy seen after pericarditis was markedly attenuated by EV pre-treatment; an effect attributable to suppression of fibroblast proliferation by EVs. Our study demonstrates that injection of extracellular vesicles at the time of open-chest surgery shows prominent anti-inflammatory effects and prevents AF due to sterile pericarditis. Translation of this finding to patients might provide an effective new strategy to prevent post-operative AF by reducing atrial inflammation and fibrosis.

To review the literature on treatment of venous thromboembolism (VTE) and prevention of cardioembolic stroke with direct-acting oral anticoagulants (DOACs) in low- and high-body-weight patients and to make recommendations regarding agent selection and dosing in these patient populations. Summary: The selection and optimal dosing of DOACs in low- and high-body-weight patients has not yet been fully elucidated by clinical trials; however, evidence suggests that issues of both safety and efficacy in patients at the extremes of body weight may warrant careful consideration when selecting a DOAC for such patients. This review provides a thorough discussion of the use of DOACs in the treatment of VTE and prevention of cardioembolic stroke in patients at the extremes of body weight and provides guidance regarding agent selection. Conclusion: While the published evidence on use of DOACs in patients at extremes of body weight is sparse, apixaban and rivaroxaban appear to have the most favorable safety and efficacy profiles. Edoxaban and dabigatran should be avoided.

Atrial fibrillation (AFIB) is the most common heart rhythm abnormality and is associated with significant morbidity and mortality. While the treatment of AFIB involves strategies of rate with or without rhythm control, it is also essential to strategize appropriate therapies to prevent thromboembolic complications arising from AFIB. Previously, anticoagulation was the main treatment option which exposed patients to higher than usual risk of bleeding. However, with the advent of new technology, novel therapeutic options aimed at surgical or percutaneous exclusion or occlusion of the left atrial appendage in preventing thromboembolic complications from AFIB have evolved. This review evaluates recent advances and therapeutic options in treating AFIB with a special focus on both surgical and percutaneous interventions which can reduce and/or eliminate thromboembolic complications of AFIB.

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.