Atrial fibrillation (AF) is the commonest rhythm disturbance of the heart, and is a major cause of serious morbidity such as congestive heart failure and cerebrovascular embolism (`stroke'). Importantly, the incidence of this arrhythmia increases with age, with the result that AF is fast becoming the latest `epidemic'in an aging population. The diagnosis and management of AF have therefore become an important and challenging aspect of cardiovascular medicine. However, progress in effectively treating AF has been slow, in large part due to a poor understanding of the underlying mechanisms of this arrhythmia. In this regard, recent studies indicate an important role for the pulmonary veins and the posterior left atrium (PLA) in the genesis of this arrhythmia. Several pioneering ablative procedures have therefore been performed in the PLA, albeit with mixed success. In the heart, G protein coupled receptors (GPCRs) and their cognate signaling partners, the heterotrimeric G-proteins, regulate most mechanical and electrical functions. The autonomic nervous system regulates critical cardiac parameters such as excitability, heart rate, force of contraction, conduction velocity and refractoriness. Activation of 2-adrenergic receptors, which are coupled to G1s, leads to an increase in conduction velocity and several other excitatory responses in the heart. Activation of muscarinic M2 receptors, which are coupled to G1i, leads to a marked shortening of refractoriness in the atria. In combination, these two limbs of the autonomic nervous system have been demonstrated to create substrate for AF. Thus, the adrenergic and muscarinic receptors or their partners G1i and G1s may be viable alternative targets for therapeutic strategies designed to modulate arrhythmogenic influences in the heart. The PLA may be an especially attractive target for these strategies, on account of a very robust and unique autonomic profile that is thought to be conducive to AF. In an attempt to modify substrate for AF, we propose to use novel peptides directed at the GPCR/G protein interface to selectively inhibit parasympathetic or sympathetic pathways in the PLA. Using minigenes (plasmids) that can express these G-protein inhibitory peptides on both a short and long term basis, the proposed studies will be performed in both an acute as well as a chronic model of AF. In the acute experiments (Aim 1), localized injection of minigene into the PLA will be performed in order to inhibit vagally or adrenergically-mediated AF in normal dogs.
In Aim 2, we propose to use these minigenes in a canine model of chronic AF;minigenes under the control of a long-acting promoter will be injected locally into the PLA, to prevent the development of autonomic substrate for AF. The proposed studies are an important stride towards identifying novel therapeutics that may eventually be applied to the treatment of life threatening arrhythmias.

Public Health Relevance

Atrial fibrillation (AF) is the commonest rhythm disturbance of the heart, and is a major cause of serious morbidity such as congestive heart failure and stroke. However, currently available treatment options for AF are not very effective. We propose a new method to treat AF, by using a novel peptide (protein) to inhibit the function of the nerves that trigger this arrhythmia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093490-05
Application #
8444322
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Wang, Lan-Hsiang
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$432,300
Indirect Cost
$149,087
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Tomson, Todd T; Arora, Rishi (2016) Modulation of Cardiac Potassium Current by Neural Tone and Ischemia. Card Electrophysiol Clin 8:349-60
Kunamalla, Aaron; Ng, Jason; Parini, Vamsi et al. (2016) Constitutive Expression of a Dominant-Negative TGF-β Type II Receptor in the Posterior Left Atrium Leads to Beneficial Remodeling of Atrial Fibrillation Substrate. Circ Res 119:69-82
Arora, Rishi; Knight, Bradley P (2015) Epicardial atrial fat: not quite as idle as it looks. Heart Rhythm 12:266-7
Arora, Rishi; Yancy, Clyde W (2015) Treatment: special conditions: co-existing heart disease: atrial fibrillation. J Am Soc Hypertens 9:313-7; quiz 318-9
Gordon, David; Goldberger, Jeffrey J; Arora, Rishi et al. (2015) Searching for "order" in atrial fibrillation using electrogram morphology recurrence plots. Comput Biol Med 65:220-8
Ng, Jason; Gordon, David; Passman, Rod S et al. (2014) Electrogram morphology recurrence patterns during atrial fibrillation. Heart Rhythm 11:2027-34
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Arora, Rishi (2013) How the pulmonary veins 'talk' to the sinoatrial node: new insights into an old mystery. Cardiovasc Res 99:380-1
Ng, Jason; Passman, Rod S; Arora, Rishi et al. (2012) Paradoxical change in atrial fibrillation dominant frequencies with baroreflex-mediated parasympathetic stimulation with phenylephrine infusion. J Cardiovasc Electrophysiol 23:1045-50
Koduri, Hemantha; Ng, Jason; Cokic, Ivan et al. (2012) Contribution of fibrosis and the autonomic nervous system to atrial fibrillation electrograms in heart failure. Circ Arrhythm Electrophysiol 5:640-9

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