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Signal transduction pathways are at the core of most biological processes and are critical regulators of heart physiology and pathophysiology. The heart is both a transmitter and dynamic receptor of a variety of intracellular and extracellular stimuli, playing a critical role of an integrator of diverse signaling mechanisms. Alterations in signaling pathways are contributing factors in the development and progression of a broad spectrum of diseases, ranging from dysrhythmias and atherosclerosis to hypertension and the metabolic syndrome. Targeting specific components of these signaling pathways has been shown to be effective in preclinical studies with significant therapeutic impact.