The Complexities of cAMP Signaling in the Heart

The autonomic nervous system regulates heart function to meet the metabolic demands of the body. The sympathetic branch of the autonomic nervous system provides an increase in ventricular force of contraction and rate of relaxation. These changes in contractility occur through the activation of cardiac adrenergic receptors (ARs), which can be divided into two types: (ARs) or (ARs). ARs, the more prominent ARs in the heart, utilize the diffusible second messenger molecule 3',5'-cyclic adenosine monophosphate (cAMP) to translate sympathetic stimulation to changes in cardiac functional properties. 1ARs, which is the only AR subtype expressed in the heart, also produce small functional changes and cardioprotective effects in the case of heart disease. Traditionally, 1ARs signal through a different modality from ARs. However, 1AR stimulation has been previously shown to inhibit AR cardiac functional changes. The first part of this dissertation presents an investigation into whether 1ARs can also regulate cAMP through a non-canonical signaling pathway. The second portion of this dissertation delves deeper into the mechanisms of AR subtype (1AR or 2AR) regulation of cAMP signaling. I hypothesized that intracellularly segregated cAMP microdomains allow for the unique set of functional effects seen from selective stimulation of each AR subtype. To answer these questions, I utilized cAMP sensitive fluorescence resonance energy transfer (FRET)-based biosensors with live cell imaging techniques. Using the non-targeted cytosolically expressed Epac2-camps FRET biosensor, I was able to demonstrate that 1ARs can indeed control basal and AR induced cAMP levels through a tyrosine kinase mediated pathway that works at the level of the AR. Furthermore, I characterized a novel FRET biosensor, Epac2-KAP, which is targeted to the non-junctional sarcoplasmic reticulum. The application of the two biosensors allowed for the confirmation of a compartmentalized 2AR cAMP signal due in part to the activity of phosphodiesterase types 2 and 3. The findings documented in this dissertation provide important advancements in the understanding of the regulation of cardiac cAMP signaling through receptor and compartmentation mechanics. Leveraging these discoveries could lead to a better understanding of heart disease and the possible development of therapeutic treatments

SPEAR Trial: Smartphone Pediatric ElectrocARdiogram Trial.

Smartphone-enabled ECG devices have the potential to improve patient care by enabling remote ECG assessment of patients with potential and diagnosed arrhythmias. This prospective study aimed to assess the usefulness of pediatric ECG tracings generated by the AliveCor device (Oklahoma City, OK) and to assess user satisfaction.Enrolled pediatric patients with documented paroxysmal arrhythmia used the AliveCor device over a yearlong study period. Pediatric electrophysiologists reviewed all transmitted ECG tracings. Patient completed surveys were analyzed to assess user satisfaction.35 patients were enrolled with the following diagnoses: supraventricular tachycardia (SVT, 57%), atrial fibrillation (AF, 11%), ectopic atrial tachycardia (EAT, 6%), atrial tachycardia (AT, 3%), and ventricular tachycardia (VT, 23%). A total of 238 tracings were received from 20 patients, 96% of which were of diagnostic quality for sinus rhythm, sinus tachycardia, SVT, and AF. 126 patient satisfaction surveys (64% from parents) were completed. 98% of the survey responses indicated that it was easy to obtain tracings, 93% found it easy to transmit the tracings, 98% showed added comfort in managing arrhythmia by having the device, and 93% showed interest in continued use of the device after the study period ended.Smartphone-enabled ECG devices can generate tracings of diagnostic quality in children. User satisfaction was extremely positive. Use of the device to manage certain patients with AF and SVT showcases the future role of remote ECGs in the successful outpatient management of arrhythmias in children by potentially reducing Emergency Department visits and healthcare costs

Patient characteristics.

<p>Patient characteristics.</p

Transmission interpretations according to patient diagnoses.

<p>SVT, supraventricular tachycardia; AF, atrial fibrillation; EAT, ectopic atrial tachycardia; AT, atrial tachycardia; VT, ventricular tachycardia.</p><p>Transmission interpretations according to patient diagnoses.</p

Samples of transmitted ECG tracings.

<p>A) Atrial fibrillation. B) Supraventricular tachycardia.</p

User satisfaction survey results.

<p>Comparison of different user satisfaction categories between those who transmitted and those who did not transmit.</p