MOLECULAR POLARIZATION IN DYSSYNCHRONOUS HEARTS AND CRT

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This subproject focuses on defining the influence and mechanisms whereby cardiac dyssynchrony with and without underlying cardiac failure induces local molecular and cellular transmural abnormalities. This project stems from our recent discovery that dyssynchrony in a failing heart results in striking localized changes in the expression of proteins involved with calcium handling, hypertrophic signaling, and electrical conduction. These changes are particularly concentrated in the endocardial layer of the late-activated territory, the region predicted to have the highest level of wall stress. Neighboring mid-epicardial tissue displays expression more akin to that observed in the opposing wall (both epi and endo layers). This highlights a localized transmural molecular polarization that can serve as an important substrate for why dyssynchrony is a major risk in heart failure patients. In addition to providing a more comprehensive analysis of the ventricular molecular and cellular effects from dyssynchrony in failure, this subproject will test the reversibility of these changes by means of cardiac resynchronization. There are three specific aims. The first aim will identify signaling cascades triggered in the dyssynchronous heart, clarify their specificity to endocardial layers in late (high stress)-activated myocardium, and determine the synergistic role of co-existing dilated cardiac failure. Two major strategies are used: specific testing of candidate proteins/genes involved with growth, remodeling, and myocyte calcium handing, and a broader analysis of myocyte sub-proteome (cytosolic, sarcomplasmic reticulum, gap junction) and transcriptome (canine array chip). The second aim will integrate these molecular findings with direct analysis of the cellular functional and calcium handling impact of dyssynchrony in cardiomyocytes derived from early versus late activated territories from both endocardial and mid-wall layers. The third aim tests the reversibility of molecular and cellular abnormalities induced by dyssynchrony by a subsequent period of cardiac bi-ventricular resynchronization. These studies will provide the first test of such reversibility, and integrate changes at molecular and cellular levels to at the whole organ level.