The long-term goal of this work is to non-invasively identify the substrate that predisposes to atrial fibrillation (AF) before the development of irreversible change in order to provide early preventative intervention. The incidence of both AF and heart failure (HF) has reached epidemic proportion, and both diseases are highly associated. Therefore, early preventative management of AF in the setting of HF is of great medical and socioeconomic importance. Atrial remodeling plays a central role in the pathophysiology of AF, especially in the setting of HF. However once atrial fibrosis develops it is often irreversible, thereby rendering preventative therapy ineffective. There are currently no non-invasive modalities that allow accurate assessment of atrial structural remodeling before the onset of permanent fibrosis. We propose a novel approach for the evaluation of the vulnerable atrial substrate in HF based on in vivo imaging of molecular mechanisms involved in inflammation and extracellular matrix remodeling. Using hybrid 64-slice hybrid SPECT/CT imaging targeted at detection of matrix metalloproteinase (MMP) activation, we will study the spatiotemporal evolution of the atrial structural remodeling process following myocardial infarction (MI) and correlate it with AF inducibility. The central hypothesis of this work is that atrial structural remodeling post-MI can be accurately detected early before the onset of atrial fibrosis and pharmacologically altered thereby reducing AF vulnerability.
In Aim 1 we will quantify the progression of the atrial remodeling process during the development of HF post-MI using non-invasive molecular imaging targeting MMP activation in relation to serum and tissue measures of MMP activation, collagen turnover, and late gadolinium enhancement MR (LGEMR) of atria.
Aim 2 will attempt to correlate the non-invasive assessment of atrial MMP activation with AF vulnerability. Finally, Aim 3 is to utilize molecular imaging to assess the effet of selective inhibition of the renin-angiotensin pathway on atrial MMP activation and AF vulnerability. We believe that targeted molecular imaging will allow early identification of the vulnerable atrial substrate. As such it may help identify and stratify those at risk for developmen of AF before the onset of irreversible structural changes, thereby allowing early preventative intervention.

Public Health Relevance

Atrial fibrillation is the most common sustained arrhythmia in humans and is a major cause of stroke, cardiovascular morbidity and mortality. This project will develop a novel approach for the evaluation of atrial structural remodeling based on the non-invasive imaging of molecular mechanisms involved in inflammation and the remodeling process. The long-term goal of this work is to non-invasively identify the substrate that predisposes to atrial fibrillation before the development of irreversible damage in order to provide early preventative intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL113352-01A1
Application #
8440270
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Danthi, Narasimhan
Project Start
2013-02-01
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$669,036
Indirect Cost
$235,934
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520