Atrial fibrillation: Epigenetic aspects and role of sodium-glucose cotransporter 2 inhibitors.

Atrial fibrillation (AF) is the most frequent arrhythmia and is associated with substantial morbidity and mortality. Pathophysiological aspects consist in the activation of pro-fibrotic signaling and Ca2+ handling abnormalities at atrial level. Structural and electrical remodeling creates a substrate for AF by triggering conduction abnormalities and cardiac arrhythmias. The care of AF patients focuses predominantly on anticoagulation, symptoms control and the management of risk factors and comorbidities. The goal of AF therapy points to restore sinus rhythm, re-establish atrioventricular synchrony and improve atrial contribution to the stroke volume. New layer of information to better comprehend AF pathophysiology, and identify targets for novel pharmacological interventions consists of the epigenetic phenomena including, among others, DNA methylation, histone modifications and noncoding RNAs. Moreover, the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in diabetic and non-diabetic patients at cardiovascular risk as well as emerging evidence on the ability of SGLT2i to modify epigenetic signature in cardiovascular diseases provide a solid background to investigate a possible role of this drug class in the onset and progression of AF. In this review, following a summary of pathophysiology and management, epigenetic mechanisms in AF and the potential of sodium-glucose SGLT2i in AF patients are discussed.

Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury.

The role of endogenous c-Kit receptor activation on cardiac cell homeostasis and repair remains largely unexplored. Transgenic mice carrying an activating point mutation (TgD814Y) in the kinase domain of the c-Kit gene were generated. c-Kit(TgD814Y) receptor was expressed in the heart during embryonic development and postnatal life, in a similar timing and expression pattern to that of the endogenous gene, but not in the hematopoietic compartment allowing the study of a cardiac-specific phenotype. c-Kit(TgD814Y) mutation produced a constitutive active c-Kit receptor in cardiac tissue and cells from transgenic mice as demonstrated by the increased phosphorylation of ERK1/2 and AKT, which are the main downstream molecular effectors of c-Kit receptor signaling. In adult transgenic hearts, cardiac morphology, size and total c-Kit(+) cardiac cell number was not different compared with wt mice. However, when c-Kit(TgD814Y) mice were subjected to transmural necrotic heart damage by cryoinjury (CI), all transgenic survived, compared with half of wt mice. In the sub-acute phase after CI, transgenic and wt mice showed similar heart damage. However, 9 days after CI, transgenic mice exhibited an increased number of c-Kit(+)CD31(+) endothelial progenitor cells surrounding the necrotic area. At later follow-up, a consistent reduction of fibrotic area, increased capillary density and increased cardiomyocyte replenishment rate (as established by BrdU incorporation) were observed in transgenic compared with wt mice. Consistently, CD45(-)c-Kit(+) cardiac stem cells isolated from transgenic c-Kit(TgD814Y) mice showed an enhanced endothelial and cardiomyocyte differentiation potential compared with cells isolated from the wt. Constitutive activation of c-Kit receptor in mice is associated with an increased cardiac myogenic and vasculogenic reparative potential after injury, with a significant improvement of survival.