Contractile dysfunction early after large myocardial infarction (MI) is not limited to necrotic tissue, but extends also to non-ischemic zones of the left ventricle (LV) remote from the ischemic region. We hypothesize that reactive oxygen species (ROS) and pro-inflammatory cytokines and elaborated by leukocytes infiltrating the heart after reperfused MI play a key role in the pathophysiology of this reversible form of LV dysfunction. We propose that whole-animal experiments employing a complementary set of pharmacologic and genetic approaches will help to elucidate the role of inflammatory activation in remote zone LV dysfunction post-MI and to identify effective treatment strategies for preserving LV function after large MI. In preliminary studies, our partnership has developed a mouse model of remote zone LV dysfunction after reperfused MI and has validated it using cardiac magnetic resonance imaging (MRI). Using MRI in combination with molecular techniques, the functions of oxidative stress, TNF-alpha, NF-kappaB, and iNOS will be evaluated using specific pharmacologic agents and genetically manipulated mice. A multidisciplinary approach will be used that encompasses the fields of biomedical engineering, radiology, cardiovascular physiology, pharmacology, immunopathology, cell biology and molecular genetics.
The specific aims are to: 1) Validate a novel cardiac MRI pulse sequence and use it to define the time course of remote zone LV dysfunction in mice. While our preliminary MRI studies show that remote LV dysfunction resolves within 7 days after MI, we propose to apply a newly-developed CSPAMM-based DENSE pulse sequence to assess regional contractile function at even higher resolution. 2) Probe the pathophysiology of remote zone LV dysfunction post-MI using a pharmacologic approach. We hypothesize that pharmacologic agents capable of controlling oxidant stress, blocking TNF-a, inhibiting NF-?B and/or suppressing iNOS will preserve contractile function in remote, non-infarcted regions of the LV after large MI. 3) Probe the pathophysiology of remote zone LV dysfunction post-MI using genetic approaches. In preliminary studies, we have shown that contractile function in the remote LV is preserved in iNOS knock-out mice after large MI. Similarly, we hypothesize that remote LV function after MI will be preserved in TNF-a knock-outs, in mice with impaired NF-?B signaling, and in transgenic mice overexpressing SOD. Gene therapy with an Ad5 vector expressing SOD should yield similar results. 4) Determine the role of hematopoietic cells in remote zone LV dysfunction using bone marrow chimeras. We hypothesize that the beneficial effects of the genetic interventions investigated in Aim 3 may not depend entirely on hematopoietic cells, and propose a series of bone marrow transplantation experiments with iNOS knock-out mice to address this possibility.
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