Atrial fibrillation (AF) is the most common supraventricular tachyarrhythmia that can present without cardiovascular disease (lone AF). Frequent high-intensity endurance exercise is a risk factor for lone AF, and the pathophysiology of AF induced by intense endurance exercise is unknown. We found that after 6 weeks of intense swimming and running, mice were far more susceptible to AF, but not ventricular arrhythmias. Exercise induced atrial fibrosis, inflammation and slowed conduction without detectible changes in ventricles. Since AF is associated with stretch and since a tumor necrosis factor-α (TNFα) is a mechanosensitive inflammatory factor, mice were treated with the TNFα inhibitor etanercept. Etanercept treatment blocked inflammation, fibrosis, and AF vulnerability in the exercised mice. Consistent with these findings, we found that exercise caused large elevations in atrial pressures. Our findings support the conclusion that mechanical loading of atria during exercise induces TNFα release, leading to structural remodeling and enhanced AF vulnerability.

Heart rate is modulated by the opposing activities of sympathetic and parasympathetic inputs to pacemaker cardiomyocytes in the sinoatrial (SA) node. Parasympathetic activity on nodal myocytes is mediated by acetylcholine-dependent stimulation of M2 muscarinic receptors and activation of Gαi/o signalling. Although, regulators of G-protein signalling (RGS) proteins are potent inhibitors of Gαi/o signalling in many tissues, the RGS protein(s) that regulate parasympathetic tone in the SA node are unknown. Our results demonstrate that RGS4 mRNA levels are higher in the SA node compared to right atrium. Conscious freely moving RGS4-null mice showed a greater extent of bradycardia in response to parasympathetic agonists compared to wild-type animals. Moreover, anaesthetized rgs4-null mice had lower baseline heart rates and greater heart rate increases following atropine administration. Retrograde-perfused hearts from rgs4-null mice also showed enhanced negative chronotropic responses to carbachol, while isolated SA node myocytes showed greater sensitivity to carbachol-mediated reduction in the action potential firing rate. Finally, rgs4-null SA node cells showed decreased levels of G-protein-coupled inward rectifying potassium (GIRK) channel desensitization, and altered modulation of acetylcholine-sensitive potassium current (IKACh) kinetics following carbachol stimulation. Taken together, our studies establish that RGS4 plays an important role in regulating sinus rhythm by inhibiting parasympathetic signalling and IKACh activity. Following these results, we predicted that loss of RGS4 expression and function will result in increased levels of parasympathetic effector activity leading to increased susceptibility to atrial fibrillation. Susceptibility to atrial fibrillation (AF) depends strongly on parasympathetic activity. Since RGS4 inhibits parasympathetic / M2-dependent Gαi/o signalling in the SA node, we explored whether changes in RGS4 levels altered the susceptibility of atrial fibrillation. We found that, RGS4 levels were decreased in atria of tachypaced dogs prior to their development of chronic AF. Moreover, in vivo ECG recordings of anaesthetized mice showed greater susceptibility to AF while optical mapping of isolated atrial preparations using a voltage-sensitive dye revealed greatly increased susceptibility to rotor formation when RGS4 was ablated. Consistent with altered parasympathetic signalling in the myocardium of rgs4-null mice, IKACh evoked by carbachol application were greater in isolated atrial myocytes from rgs4-null mice. These IKACh changes were, as expected, associated with marked action potential duration shortening in response to parasympathetic activation, but not to slower conduction velocities. Together, our findings establish that RGS4 protects atrial tissues from excess parasympathetic signalling that predispose to atrial fibrillation.

Thesis (Ph. D.)--University of Pennsylvania, 1916. / "From the John Herr Musser Department of Research Medicine, University of Pennsylvania, Philadelphia."

Thesis (Ph. D.)--University of Pennsylvania, 1916. / "From the John Herr Musser Department of Research Medicine, University of Pennsylvania, Philadelphia."

The ablative management of atrial fibrillation, despite a number of landmark discoveries, remains one of the most challenging fields in interventional electrophysiology. It is generally accepted that successful isolation of the pulmonary veins is a highly effective way of managing paroxysmal forms of AF. However, despite almost a decade of research into alternative lesion patterns, the solution to persistent AF remains beyond our grasp. A variety of strategies have been proposed to target key areas in the atria; these use various complex mapping systems, usually based on tailored lesion sets to try and improve outcomes. None have proven to be the golden bullet. We have investigated the role of a lesion set intended to alter the electrical properties of the posterior wall of the left atrium. Commonly known as the ‘box-set’, this pattern has shown promise in early studies and may provide some key insights into future developments. Surgical ablation using the Epicor system aims to deliver the box-set lesion, outcomes have previously been documented but each series has its limitations. In our series, very late outcomes are reported to show an 80% freedom from AF rate in patients with paroxysmal AF pre-operatively and only 20% in those with long-standing persistent forms. The reason behind this dramatic variation is explored through the invasive electrophysiologal assessment of both successful and unsuccessful cases. We report a clear correlation between the successful isolation of the posterior wall and long-term freedom from AF. Though surgical ablation may be an acceptable approach for some, the ultimate goal is a lesion set that can be delivered purely endocardially. We explore the outcome of one such empirical pattern based on the box-set concept delivered through linear catheter technology and report outcomes broadly similar to alternative patterns.

Cardiovascular disease is prevalent across the western world and is a major cause of morbidity and mortality, accounting for approximately a third of all fatalities. Investigating the heart by simulating its electrophysiology via the aid of mathematical models has advanced significantly over the past 60 years and is now a well established field. While much of the research focus is placed on the ventricles, the study of the atria is in comparison neglected. Therefore this Thesis is focused on the genesis and maintenance of atrial fibrillation (AF). A series of case studies are performed whereby established biophysically detailed mathematical models are implemented and modified to incorporate electrophysical alterations of atrial cells resulting from a variety of external conditions. The opening section of this Thesis is dedicated to developing a background to the field, including a discussion into the clinical aspect of the diagnosis and management of AF. The suitability of two atrial cell models is discussed and the development of single cell, 1D, 2D, and 3D multi-scale simulation protocols are described in detail. In addition measurements taken to quantify the arrhythmogenic properties of the cells susceptibility to AF are outlined. The second section is focused on the incorporation of conditions thought to enhance atrial tissues ability to initiate and maintain the genesis of AF. Included is a case study into the missence S140G gene mutation, and elevated physiological levels of the hormone Homocystein. The third section investigates the effectiveness of well established and widely used pharmacological treatments such as Beta-Blockers. In addition possible avenues of investigations for the development of atrial specific drugs are explored. These include blocking of the ultra rapid potassium channel and a more novel target for therapy via the targeting of 5HT4 receptors; which is transcribed solely in the atria and alters the electrophysical properties of the L-type Calcium current. The final part of this Thesis is dedicated to the development of a 2D atrial sheet model which includes electrical and spatial heterogeneities via the inclusion of multiple cell types and basic fiber orientation respectively. This allows for an investigation into the role that heterogeneities play in role genesis and maintenance of AF. The main finding of this Thesis is that alterations to the electrophysiology of atrial cells, due to external factors, can be successfully simulated via the implementation of mathematically detailed atrial cell models. It is concluded that simulations of the KENQ1 mutation and elevated levels of Homocystein successfully reproduce conditions which increase the onset of AF. Established treatments such as Beta-Blockers are found to have limited effectiveness. Possible theoretical treatments, such as the blocking of IKur, are found to provide a small amount of therapeutic benefit. In contrast, investigations into the effects of Serotonin were inconclusive. The study into the 2D atria indicated the importance that heterogeneities play in atria. The conclusions show that models provide a powerful tool when investigating how changes to electrophysiology of cells are manifested at a multi-scale level. The models also have their limitations and require further advancement to improve their accuracy.

No description available.

There are in excess of one million people across the UK people living with atrial fibrillation (AF), a long term condition that can lead to stroke and other complications, costing the NHS over £2,200 million per year. However little is known about the experience of living with AF and what patients' perceptions are of the support they receive from health professionals. In order to ensure that patients have the best possible experience of care, healthcare professionals need to have an understanding of how patients view their condition and the type of support they would like to receive from the professionals involved in their care. Although there has been a significant amount of work investigating social support for people with health conditions, there has been little work exploring support provided by healthcare professionals, defined in this study as professional support. This study aimed to investigate and assess the professional support needs of people with AF to develop knowledge and understanding in this field. A theoretical framework for professional support was developed based on the tri-dimensional model of social support and was used to direct the research. Using an exploratory sequential design, a two phase mixed methods study was undertaken. Initially, qualitative interviews were undertaken with patients recruited from outpatient arrhythmia clinics at one National Health Service (NHS) hospital and identified from the perspective of the patient how, when and where healthcare professionals did/did not provide support. Key components of emotional, informational and tangible professional support were identified from thematic analysis of the interview data and used to inform the development of a quantitative questionnaire. Physical activity, exercise and the impact of AF on activity levels were identified by participants as important and so were also included. The quantitative online questionnaire was completed by patient members of the Atrial Fibrillation Association (AFA). To examine relationships between variables, statistical analyses were performed using Fisher's exact test and indicated that people with AF had a range of emotional, informational and tangible professional support needs. Different subgroups of people with AF had different professional support needs: People with more severe symptoms needed more emotional support as well as more tangible support and people with paroxysmal AF needed more informational support. People undergoing ablation as treatment for their AF had specific informational and emotional needs for support. AF played a significant part in the lives of people with AF by modifying activities of daily living and shaping physical activity behaviour and choice of activities. People with AF therefore needed professional support in maintaining and/or increasing their levels of activity. Considering the specificity of professional support, GPs, cardiologists and arrhythmia nurse specialists were identified as most supportive, with GPs and cardiologists also considered as the least helpful at providing support, indicating a variation in professional support. The findings from this study contribute to the limited body of knowledge describing the experience of living with AF and provide healthcare professionals with a unique understanding of how best to provide professional support. The tri-dimensional model provides detailed knowledge of the components of informational, emotional and tangible support that people with AF would like to receive from the healthcare professionals involved in their care. The findings indicate there are differing support needs for different subsets of people with AF demonstrating a need for individualised professional support. The theoretical framework for professional support used in this study provides a model that could be used in future research studies to identify the types of professional support required by patients and to identify subgroups of patients who may require additional professional support. By accurately identifying the needs of patients, this will ensure that healthcare professionals are able to deliver effective patient centred services, leading to an improved patient experience and the delivery of high quality patient care.

The aim of this thesis was to describe and explore how the partner relationship of patient–partner dyads isaffected following cardiac disease and, in particular, atrial fibrillation (AF) in one of the spouses. The thesis is based on four individual studies with different designs: descriptive (I), explorative (II, IV), and cross-sectional (III). Applied methods comprised a systematic review (I) and qualitative (II, IV) and quantitative methods (III). Participants in the studies were couples in which one of the spouses was afflicted with AF. Coherent with a systemic perspective, the research focused on the dyad as the unit of analysis. To identify and describe the current research position and knowledge base, the data for the systematic review were analyzed using an integrative approach. To explore couples’ main concern, interview data (n=12 couples) in study II were analyzed using classical grounded theory. Associations between patients and partners (n=91 couples) where analyzed through the Actor–Partner Interdependence Model using structural equation modelling (III). To explore couples’ illness beliefs, interview data (n=9 couples) in study IV were analyzed using Gadamerian hermeneutics. Study I revealed five themes of how the partner relationship is affected following cardiac disease: overprotection, communication deficiency, sexual concerns, changes in domestic roles, and adjustment to illness. Study II showed that couples living with AF experienced uncertainty as the common main concern, rooted in causation of AF and apprehension about AF episodes. The theory of Managing Uncertainty revealed the strategies of explicit sharing (mutual collaboration and finding resemblance) and implicit sharing (keeping distance and tacit understanding). Patients and spouses showed significant differences in terms of self-reported physical and mental health where patients rated themselves lower than spouses did (III). Several actor effects were identified, suggesting that emotional distress affects and is associated with perceived health. Patient partner effects and spouse partner effects were observed for vitality, indicating that higher levels of symptoms of depression in patients and spouses were associated with lower vitality in their partners. In study IV, couples’ core and secondary illness beliefs were revealed. From the core illness belief that “the heart is a representation of life,” two secondary illness beliefs were derived: AF is a threat to life, and AF can and must be explained. From the core illness belief that “change is an integral part of life,” two secondary illness beliefs were derived: AF is a disruption in our lives, and AF will not interfere with our lives. Finally, from the core illness belief that “adaptation is fundamental in life,” two secondary illness beliefs were derived: AF entails adjustment in daily life, and AF entails confidence in and adherence to professional care. In conclusion, the thesis result suggests that illness, in terms of cardiac disease and AF, affected and influenced the couple on aspects such as making sense of AF, responding to AF, and mutually incorporating and dealing with AF in their daily lives. In the light of this, the thesis results suggest that clinicians working with persons with AF and their partners should employ a systemic view with consideration of couple’s reciprocity and interdependence, but also have knowledge regarding AF, in terms of pathophysiology, the nature of AF (i.e., cause, consequences, and trajectory), and treatments. A possible approach to achieve this is a clinical utilization of an FSN based framework, such as the FamHC. Even if a formalized FSN framework is not utilized, partners should not be neglected but, rather, be considered a resource and be a part of clinical caring activities. This could be met by inviting partners to take part in rounds, treatment decisions, discharge calls or follow-up visits or other clinical caring activities. Likewise, interventional studies should include the couple as a unit of analysis as well as the target of interventions.

BACKGROUND: Atrial Fibrillation (AF) is the most common cardiac arrhythmia, affecting over 3 million Americans. Many people who suffer from AF have pre-disposing factors such as hypertension, ischemia, and structural heart disease, but recent research has also demonstrated the importance of genetic factors that can contribute to AF. In the present study, we sought to determine the causative mutation in a family with AF, atrial septal, and ventricular septal defects. METHODS: We evaluated a pedigree with 16 family members, one of whom had an ASD, one a VSD, and three had AF. Exome sequencing was performed on three of the five affected family members followed by confirmation with Sanger sequencing in all family members. A separate cohort from the MGH AF Study with early-onset AF (age at onset 47.1 ± 10.9 years, 79.3% male) was also screened for mutations using a combination of Sanger sequencing and high resolution melting. Variants were then functionally characterized using reporter assays in a mammalian cell line using wild-type and mutant constructs driving NPPA, αMHC and NPPB promoter reporters. RESULTS: Exome sequencing of the three affected individuals in the family identified a highly conserved mutation, R585L, in the transcription factor gene, GATA6. We also identified three additional GATA6 variants (P91S, A177T, and A543G) in the cases with early-onset AF from the MGH AF Study. We found that three of the four variants had a marked upregulation of luciferase activity (R585L; 4.1 fold, p<0.0001; P91S; 2.5 fold, p=0.0002; A177T; 1.7 fold, p=0.03). Additionally, when co-overexpressed with GATA4 and MEF2C, all GATA6 variants exhibited upregulation of the αMHC and NPPA activity compared to control. CONCLUSION: Overall, we found gain-of-function mutations in GATA6 in both a family with early-onset AF and atrioventricular septal defects as well as in patients with sporadic, early-onset AF. This evidence suggests that specific gain of function mutations in GATA6 contribute to the development of AF. / 2017-06-16T00:00:00Z