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.

Atrial fibrillation (AF) is one of the most frequent complications following coronary artery bypass grafting (CABG), occurring in up to 40% of patients. This thesis investigates the utility of non-invasive markers of left ventricular filling pressure in predicting AF in this setting, and assesses a novel marker of inflammation in the same role. Given the haemodynamic changes occurring peri-operatively it was hypothesised that acute changes in left ventricular filling pressure (LVFP), and resulting atrial stretch, might predispose to post-operative AF. Levels of the natriuretic peptides, BNP and NT-proBNP, were measured pre-operatively in 275 patients undergoing non-emergency CABG, and detailed echocardiographic examination performed. The natriuretic peptides were higher in patients who developed AF, and both were independently predictive of post-operative AF in multivariable analysis. However, their clinical utility appears modest in this role. The only significant echocardiographic predictors of AF were the transmitral E to A-wave ratio and the early mitral annulus velocity. None of the echocardiographic parameters remained independently predictive in multivariable analysis. The strongest echocardiographic correlate of both BNP and NT-proBNP was the left atrial volume index (LAVi), a marker of chronic LV filling pressure. Patients undergoing CABG are subject to a significant peri-operative inflammatory response. This was investigated in the same cohort by means of the neutrophil/lymphocyte (N/L) ratio. Patients who developed AF had greater pre- and post-operative N/L ratios, with no preoperative differences observed in other white blood cell parameters or C-reactive protein. In multivariate models, a greater post-operative N/L ratio was independently associated with the incidence of AF. In patients undergoing CABG, AF remains difficult to predict from pre-operative variables, although age appears to be a consistent factor. Difficulties in the prediction of AF in this setting are likely to reflect the heterogeneity of influences on the development of the arrhythmia in this setting.

Atrial fibrillation (AF) is the most common cardiac arrhythmia that affects an estimated 33.5 million people worldwide. Despite its prevalence and economic burden, treatments remain relatively ineffective. Interventional treatments using catheter ablation have shown more success in cure rates than pharmacologic methods for AF. However, success rates diminish drastically in patients with more advanced forms of the disease. The focus of this research is to develop a mapping strategy to improve the success of ablation. To achieve this goal, I used a computational model of excitation in order to simulate atrial fibrillation and evaluate mapping strategies that could guide ablation. I first propose a substrate guided mapping strategy to allow patient-specific treatment rather than a one size fits all approach. Ablation guided by this method reduced AF episode durations compared to baseline durations and an equal amount of random ablation in computational simulations. Because the accuracy of electrogram mapping is dependent upon catheter-tissue contact, I then provide a method to identify the distance between the electrode recording sites and the tissue surface using only the electrogram signal. The algorithm was validated both in silico and in vivo. Finally, I develop a classification algorithm for the identification of activation patterns using simultaneous, multi-site electrode recordings to aid in the development of an appropriate ablation strategy during AF. These findings provide a framework for future mapping and ablation studies in humans and assist in the development of individualized ablation strategies for patients with higher disease burden.

by Kwok Fai (Simon) Leung. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1990. / Bibliography: leaves 72-99. / ACKNOWLEDGEMENTS --- p.i / ABSTRACT --- p.ii / Chapter SECTION 1: --- Literature Review / Chapter 1.1 --- Historical perspectives of ANP --- p.1 / Chapter 1.2 --- Nature of ANP --- p.5 / Chapter 1.3 --- Release of ANP --- p.13 / Chapter 1.4 --- Biological effects of ANP --- p.17 / Chapter 1.5 --- Clinical implications --- p.24 / Chapter SECTION 2: --- Effect of ANP on Left Atrium / Chapter 2.1 --- Introduction --- p.29 / Chapter 2.2 --- Methods --- p.32 / Chapter 2.3 --- Results --- p.37 / Chapter 2.4 --- Discussion --- p.44 / Chapter SECTION 3: --- Effect of ANP on Mesenteric Artery / Chapter 3.1 --- Introduction --- p.47 / Chapter 3.2 --- Methods --- p.51 / Chapter 3.3 --- Results --- p.62 / Chapter 3.4 --- Discussion --- p.66 / Chapter SECTION 4: --- General Discussion --- p.67 / Chapter SECTION 5: --- References --- p.72

The purpose of this study was to compare the heart rates of dogs presenting with spontaneous atrial fibrillation (AF) by a surface electrocardiogram (ECG) and a 24 hour ambulatory ECG (Holter recording) in order to determine if there was a difference between these two diagnostic tests. Seven dogs with clinically stable, spontaneous AF were evaluated with a 6 lead surface ECG (MAC 5000, GE® Milwaukee) and a Holter monitor (Monitor device: LifecardCE Delmar Reynolds Medical, Holter analysis:Aria Holter software). Statistical analyses, including t-tests and linear regression models, were performed using Stata® data-analysis and statistical software. When heart rates (bpm) determined by both diagnostic testing methods were compared individually and among all of the dogs, no statistically significant differences were found. Complete data for analysis were available in 4 of the 7 dogs. This study demonstrates that despite the potential superiority of Holter monitoring relative to the surface ECG for the diagnosis of cardiac arrhythmias, average heart rates were not statistically different in these 4 dogs with controlled AF. Therefore, the average HR determined by surface ECG in the hospital may be as reliable as the average HR determined by Holter monitoring in dogs with well controlled spontaneous AF.

Thesis (M. Med. Sc.)--University of Queensland, 2003. / Date on spine is 2002. Includes bibliographical references.

published_or_final_version / Medicine / Master / Master of Research in Medicine

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.

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.

Background: Obstructive sleep apnea (OSA) has been associated with atrial enlargement in response to high arterial and pulmonary pressures and increased sympathetic tone. Continuous positive airway pressure (CPAP) is the gold standard treatment for OSA; its impact on atrial electrical remodeling has not been investigated however. Signal-averaged p-wave (SAPW) is a non-invasive quantitative method to determine p-wave duration, an accepted marker for atrial electrical remodeling. The objective was to determine whether CPAP induces reverse atrial electrical remodeling in patients with severe OSA. Methods: Prospective study in consecutive patients attending the Sleep Clinic at Kingston General Hospital. All patients underwent full polysomnography. OSA-negative and severe OSA were defined as apnea-hypopnea index (AHI) < 5 events/hour and AHI ≥ 30 events/hour, respectively. In severe OSA patients, SAPW was determined pre- and post-intervention with CPAP for 4 - 6 weeks. In OSA-negative controls, SAPW was recorded at baseline and 4 - 6 weeks thereafter without any intervention. Results: A total of 19 severe OSA patients and 10 controls were included in the analysis. Mean AHI and minimum O2 saturation were 41.4 ± 10.1 events/hour and 80.5 ± 6.5% in severe OSA patients and 2.8 ± 1.2 events/hour and 91.4 ± 2.1% in controls. Baseline BMI was different between severe OSA patients and controls (34.3 ± 5.4 vs 26.6 ± 4.6 kg/m2; p < 0.001). At baseline, severe OSA patients had a greater SAPW duration than controls (131.9 ± 10.4 vs 122.8 ± 10.5 ms; p = 0.02). After CPAP intervention, there was a significant reduction of SAPW duration in severe OSA (131.9 ± 10.4 to 126.2 ± 8.8 ms; p < 0.001). In controls, SAPW duration did not change within 4 - 6 weeks. Conclusion: CPAP induced reverse atrial electrical remodeling in patients with severe OSA as represented by a significant reduction in SAPW duration. / Thesis (Master, Physiology) -- Queen's University, 2011-07-29 12:53:09.134