Mechanisms and Treatment of Cardiac Arrhythmias

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DESCRIPTION (provided by applicant): Cardiac hypertrophy is the heart's compensatory response to a variety of extrinsic and intrinsic stimuli. Cardiac hypertrophy is believed to have a compensatory function by diminishing wall stress. Yet, paradoxically, ventricular hypertrophy is associated with a significant increase in the risk of heart failure and malignant arrhythmia. Inhibition of the nuclear factor, NF-?B, has recently been investigated as one of the possible therapeutic approaches to the treatment of cardiac hypertrophy and the results, and clinical significance promise to be vast. We surmised that the use of soluble inhibitors of NF-?B would present an attractive therapeutic means to treat cardiac hypertrophy. On the other hand, NF-?B can be both anti- and pro-apoptotic in certain conditions. Therefore, the beneficial effects of NF-?B inhibitors in cardiac hypertrophy remain to be systematically investigated. Motivated by the uncertainties, and the therapeutic potential of the inhibitors of this nuclear factor, we have obtained surprising yet, exciting data which demonstrate the beneficial effects of several novel potent soluble epoxide hydrolase (sEH) inhibitors in cardiac hypertrophy. sEH catalizes the conversion of epoxyeicosatrienoic acids (EETs) to form the corresponding dihydroxyeicosatrienoic acids (DHETs). EETs are products of cytochrome P450 epoxygenases that have vasodilatory properties similar to that of endothelium-derived hyperpolarizing factor. In addition, EETs inhibit the activation of NF-?B-mediated gene transcription. Specifically, we have shown that there is an almost complete resolution of cardiac hypertrophy by sEH inhibitors independent of the antihypertensive effects. We were able to demonstrate in our preliminary findings that these compounds potently block the NF-?B activation in cardiac myocytes. Moreover, our study shows a beneficial effect of the compounds in the prevention of cardiac arrhythmias which occur in association with cardiac hypertrophy. Inspired by these initial observations, we reason that these compounds can be exploited to be used as a tool to systematically probe the possible beneficial effects of sEH inhibition in the short- and long-term treatment of cardiac hypertrophy as well as to study the mechanisms and involvement of NF-?B signaling pathway in cardiac hypertrophy. Thus, the central goal of the proposal is to use sEH inhibitors to directly test the novel concept that enhancement of endogenous EETs can be used as a mean to prevent and reverse cardiac hypertrophy and prevent the occurrence of cardiac arrhythmias via inhibition of NF-?B activation.