![]() However, the vast majority of studies have focused on subcellular cAMP heterogeneity and compartmentalization ( 16, 18– 21), and there is little understanding of macroscale heterogeneity of cAMP signaling throughout the heart, or how cAMP signaling contributes to arrhythmogenesis. The role of cAMP signaling as a key messenger in transducing cellular responses has been widely investigated, primarily with the use of fluorescence resonance energy transfer (FRET)–based reporters in isolated cardiomyocytes. cAMP activity is tightly regulated by phosphodiesterases (PDEs), which are cAMP-degrading enzymes that play a key role in subcellular cAMP compartmentalization and nanodomain signaling ( 12, 16, 17). cAMP mediates these responses via PKA phosphorylation of several targets within the cell involved in intracellular Ca 2+ handling (e.g., ryanodine receptors, phospholamban, and RAD guanosine triphosphatase) and sarcolemmal ion channels (e.g., RAD-dependent regulation of L-type Ca 2+ channels and K + channels). cAMP is an important second messenger for sympathetic control, responsible for transducing extracellular autonomic signals to functional inotropic and chronotropic responses. Sympathetic responses are finely tuned to rapidly increase cardiac output in response to physiological stress through intracellular cyclic adenosine 3′,5′-monophosphate (cAMP)–dependent protein kinase A (PKA) pathways. Despite these known sex disparities, there is a lack of mechanistic understanding of the role of biological sex in arrhythmogenesis.Īltered downstream cellular signaling responses to sympathetic activity may also promote arrhythmias ( 12– 15). In addition, female hearts have a smaller repolarization reserve and a greater dispersion of repolarization, which make females more vulnerable to long QT-related arrhythmias ( 9– 11). Sex differences in ion channel expression, including fewer K + channels and increased peak L-type Ca 2+ current in females, result in longer APD and increased vulnerability to early after depolarizations (EADs) ( 8). ![]() The processes that underlie repolarization homogeneity also vary by sex ( 6), and the incidence of and risk factors for a variety of arrhythmias are therefore sex-dependent ( 7). Anatomical and functional heterogeneity in the form of apico-basal or transmural gradients in innervation, ion channel expression, and action potential duration (APD) can lead to nonuniform sympathetic responses and heterogeneity of repolarization, thereby promoting reentrant arrhythmias ( 2– 5). In particular, heterogeneity of sympathetic activity throughout the heart can be pro-arrhythmic. Sympathetic activity is a key contributor to the initiation and maintenance of ventricular arrhythmias ( 1). Thus, our imaging approach revealed sex-dependent regional breakdown of cAMP and associated electrophysiological differences. Apical phosphodiesterase (PDE) activity was higher in female versus male hearts, and PDE inhibition prevented repolarization changes in female hearts. In contrast, female hearts showed that cAMP levels decayed faster in apical versus basal regions, which was associated with nonuniform action potential changes and notable changes in the direction of repolarization. We showed that in male hearts, cAMP was uniformly activated in response to pharmacological β-adrenergic stimulation. Here, we developed and validated a novel cardiac-specific fluorescence resonance energy transfer–based cAMP reporter mouse and a combined voltage-cAMP whole-heart imaging system. However, whether cAMP signaling occurs heterogeneously throughout the intact heart and how this drives sex-dependent functional responses are unknown. ![]() ![]() Previous studies have shown intracellular heterogeneity and compartmentalization of cAMP signaling. Cyclic adenosine 3′,5′-monophosphate (cAMP) is a key second messenger in cardiomyocytes responsible for transducing autonomic signals into downstream electrophysiological responses. ![]()
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