The cardiac peripheral conduction system (PCS) is responsible both for the coordination of cardiac contraction as well as being the origin and conduit for abnormal ventricular arrhythmias. We have developed a relevant murine myocardial infarction model, have a novel cardiomyocyte marker for the PCS using Cx40EGFP/+ transgenic which directs Enhanced Green Fluorescent Protein (EGFP) to the cardiac conduction system without affecting the wild-type phenotype (Miquerol, 2004). We have also established endpoints for the PCS phenotype: Connexin40 (specific for the PCS), cardiomyocyte size, hypertrophic response to hemodynamic load and Nkx2-5 (a cardiac transcription factor in PCS cells). Three hypotheses and specific aims are proposed: SA1 Hypothesis: That the peripheral conduction system has a maladaptive hypertrophic response after myocardial infarction (MI). SA2 Hypothesis: Reverse remodeling of the infarcted left ventricle pharmacologically will also remodel the peripheral conduction system. SA3 Hypothesis: Genetic manipulation (reduction) of the peripheral conduction system will reduce the adaptive hypertrophic phenotype.
The first aim will use a post-myocardial infarction time course with the Cx40EGFP/+ transgenic line and controls to determine changes in the PCS phenotype during the ventricular remodeling post-MI. SA1: Determine the hypertrophic response of the peripheral conduction system after myocardial infarction in terms of cell size, gap junction morphology and cardiomyocyte peripheral conduction system markers. The second specific aim will compare the PCS phenotype and response to pharmacologic therapy with 2-blockade, angiotensin converting enzyme inhibition or both. SA2: Determine the peripheral conduction system response to reverse pharmacologic remodeling using myocardial infarction and dilated non-ischemic cardiomyopathy models. The third specific aim focuses on mechanism with a Nkx2-5+/- transgenic which reduces the number of cardiomyocytes in the PCS. We also propose to manipulate isolated murine cardiomyocytes by over- expressing Nkx2-5 using adenoviral vectors to determine regulatory mechanisms. SA3: Genetically reduce the number of PCS cardiomyocytes using the Nkx2-5+/- haploinsufficient transgenic line crossed with the Cx40EGFP/+ line to directly measure the effect of both decreased Nkx2-5 and of PCS cell number post-myocardial infarction. Relevance: Heart failure and conduction disease after MI are major health issues.

Public Health Relevance

The cardiac peripheral conduction system is responsible both for the coordination of cardiac contraction as well as being the origin and conduit for abnormal ventricular arrhythmias. The advent of cardiovascular molecular biology has gathered fresh impetus into unraveling the molecular processes that regulate the genesis and integration of peripheral conduction system cardiomyocytes. This proposal takes advantage of techniques and findings of the previous funding period to examine directly the effects of myocardial infarction and systolic heart failure on the cardiac peripheral conduction system at the cellular level. Heart disease involving the cardiac conduction system is one of the leading causes of morbidity and mortality in the Veteran population and in the United States as a whole. Myocardial infarction and heart failure affect the conduction system and may lead to ventricular arrhythmias and/or inefficient myocardial contraction (i.e., dyssynchrony). This proposal's novel approach is to focus on changes in molecular anatomy in the peripheral conduction system in relevant disease models of myocardial infarction and failure, including creating myocardial infarction in transgenic mice strains that readily identify conduction system cells.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000241-03
Application #
8195564
Study Section
Cardiovascular Studies A (CARA)
Project Start
2009-04-01
Project End
2012-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
3
Fiscal Year
2011
Total Cost
Indirect Cost
Name
Ralph H Johnson VA Medical Center
Department
Type
DUNS #
039807318
City
Charleston
State
SC
Country
United States
Zip Code
29401