Thesis (M. Res. (Med.))--University of Hong Kong, 2006.

published_or_final_version / Medicine / Master / Master of Philosophy

Thesis (M. Res.(Med.))--University of Hong Kong, 2007.

Atrial fibrillation is a common arrhythmia encountered in the emergency department. In the United States, newly diagnosed cases of atrial fibrillation is projected to be 2.6 million cases in 2030 and the annual prevalence of atrial fibrillation is expected to be 12.1 million in 2030 (Colilla et al., 2013). Patients may present to the emergency department for treatment of atrial fibrillation with a variety of symptoms and therefore makes diagnosing atrial fibrillation based on symptomatology challenging for the clinician. The primary goal of this Doctor of Nursing Practice (DNP) project is to describe symptoms of atrial fibrillation in patients that seek medical treatment in the emergency department. Methods: This descriptive study contains secondary analysis of existing data derived from structured interviews that took place at two academic medical centers. This analysis included 74 patients that presented to the emergency department with symptoms suspected of acute coronary syndrome and were later diagnosed with atrial fibrillation. Descriptive statistics were used to synthesize data, while inferential statistics (bivariate tests) were used to compare symptoms between the age groups. Results: The mean age of subjects was 70 + 13 years, ranging 31 to 92 years. The majority of subjects were men (75.7%) and whites (90.5%). The most common symptoms reported by study subjects included chest discomfort (n = 50; 67.6%), followed by generalized weakness (n = 39; 52.7%) and shortness of breath (n = 39; 52.7%), and palpitations/ funny beating of the heart (n = 36; 48.6%) and unusual fatigue/ tiredness (n = 36; 48.6%). Sweating was the only symptom that was statistically significant in the younger adult group than in the older adult age group. Conclusion: The symptoms identified in this DNP project can be used to aid in identifying patients that present to the emergency with symptomatic atrial fibrillation. Further efforts for the assessment of atrial fibrillation should focus on the dissemination of common although nonspecific symptoms to facilitate the inclusion of atrial fibrillation as part of the differential diagnosis.

Objectives: To describe patient characteristics and evaluate costs and outcomes of novel oral anticoagulants compared to clinic-monitored warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation within the Scott & White Healthcare system. Methods: Patients with atrial fibrillation, CHADS₂ score ≥ 1, and a prescription claim for dabigatran, rivaroxaban, or warfarin between 2010 and 2012 were evaluated over 12 months. Patients in the warfarin cohort were enrolled in an Anticoagulation Clinic. Patients were matched 1:1 for age, CHADS₂, and gender for comparisons between groups. Baseline characteristics, medication adherence, occurrence of adverse events, and treatment costs were compared using inferential statistics. Anticoagulation control was assessed for patients in the warfarin cohort. Results: 141 and 471 patients met criteria for the novel cohort group and the warfarin group, respectively. After matching, 136 remained in each cohort. Prior to matching, compared to the warfarin cohort, the novel anticoagulant cohort had a higher proportion of male patients (63% versus 49%), and lower average CHADS₂ score (2.65 versus 3.30), while average age in both cohorts was similar (75 years). Matched cohorts had similar adherence rates (88% for novel versus 87% for warfarin). After matching, annual medication cost in 2014 US dollars for dabigatran or rivaroxaban averaged $2,658 (SD $1,494) compared to $1,066 (SD $633) for warfarin, including monitoring costs. Annual total all-cause healthcare costs averaged $23,711 (SD $22,910) for dabigatran or rivaroxaban, compared to $18,248 (SD $24,184) for warfarin. For the 95 warfarin patients with INR values, time in therapeutic range averaged 70.4%. Conclusion: Compared to clinic-monitored warfarin, more men than women were prescribed new oral anticoagulants and these patients averaged a lower CHADS₂ score. After matching, patient adherence was high and comparable between groups. Anticoagulation control for warfarin patients was similar to clinical trials. Annual medication cost was significantly greater for new oral anticoagulants than clinic-monitored warfarin, including INR monitoring costs. Total annual all-cause healthcare costs were significantly greater for patients taking new oral anticoagulants compared to warfarin, although too few adverse events occurred to draw conclusions regarding event rates and costs of ischemic stroke and major bleeds. / text

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.

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.