| Popis: |
Atrial fibrillation (AF), the most commonly encountered arrhythmia, is responsible for significant morbidity and mortality. Structural, electrical, and hereditable factors promote AF. Endothelin-1 (ET-1), a potent vasoconstrictor peptide and mitogen, also affects cardiac myocytes. In vitro, ET-1 enhances myocyte Ca2+ transients, and promotes myocyte hypertrophy and interstitial fibrosis. In translational studies based on human atrial tissues and relevant experimental models, I tested the hypothesis that atrial ET-1 content is related to atrial remodeling, AF risk and AF persistence. In human left atria (LA), ET-1 protein was increased in AF patients and was associated with AF persistence and atrial size. Microarray analysis revealed that ET-1 mRNA abundance was correlated with expression of genes involved in fibrosis and hypertrophy. The SNP rs2200733 (4q25) is associated with increased AF risk. In lone AF patients, plasma ET-1 level was associated with the risk allele of this SNP. Heart failure (HF) creates a substrate for AF. In a canine HF model due to ventricular tachypacing (VTP), atrial ET-1 was elevated prior to and during the development of HF. During VTP, the atria and pulmonary veins (PVs) showed parallel increases in ET-1, IP3R-I protein and fibrosis that were markedly higher and earlier than increases in the ventricles. ET-1 protein was present in cardiac myocytes and fibroblasts. ET-1 may have both paracrine and autocrine effects that promote electrical and structural remodeling.In a canine cardiac surgery model, we assessed the relationship of the ET-1 system and omega-3 fatty acid treatment on inflammation and AF inducibility following cardiac surgery. Following surgery, systemic inflammatory markers and ET-1 protein in the LA and PVs were increased. Increased LA ET-1 was associated with downregulation of ET-1 receptors but upregulation of IP3Rs, suggesting enhanced ET-1/IP3 signaling. Three weeks of dietary ω3-fatty acid supplement reduced inflammation and ET 1 protein levels and eliminated AF inducibility. Together, these studies clearly demonstrate that atrial ET-1 is associated with atrial fibrosis, atrial size and AF persistence. Available treatments for AF are suboptimal; these studies suggest that dietary ω3-fatty acids and/or ET-1 antagonists may attenuate AF development or progression. Additional studies are needed to test this intriguing hypothesis |
