The role of NLRP3-inflammasome signaling in different forms of atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia in developed countries, affecting more than 33 million people worldwide. It leads to increased morbidity and mortality due to complications like stroke, hemodynamic instability, heart failure and cardiomyopathy. AF represents a major public health problem negatively affecting quality of life. Traditionally, AF is defined as paroxysmal (episodes < 7 days; PAF), persistent (episodes > 7 days) and long- standing persistent (“chronic”; CAF). In addition, AF commonly occurs after surgery: post- operative atrial fibrillation (POAF). Post-operative inflammation has been suggested to be an important trigger of POAF and there is accumulating evidence for a potential role of inflammation in other forms of AF. However, the exact mechanistic role of inflammation in AF pathophysiology remains elusive.

As a well-known activator of inflammatory signaling, the “Nucleotide-binding and oligomerization (NACHT), Leucine-rich repeat (LRR) and Pyrin (PYD) domains containing protein 3” (NLRP3) inflammasome could contribute to AF. This thesis addressed the hypothesis that the NLRP3-inflammasome complex is more active in patients with AF, especially in those prone to POAF. The inflammasome components, products and activation pathways were examined using the Western blot technique in right atrial samples of 237 patients. Although protein levels of the inflammasome components - NLRP3, apoptosis-associated speck-like protein (ASC) and caspase-1 (Casp1) - were differently regulated in the distinct forms of AF compared to Ctl, in whole-tissue lysates AF patients showed significant upregulation of the major priming pathway toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), followed by enhanced purinergic receptor subtype 7 (P2X7R) triggering mechanism. Protein expression of gasdermin D (GSDMD), an important effector of the NLRP3 inflammasome, was activated in POAF and PAF, but not CAF patients. Protein levels of the cytokines interleukin-1b and -18 (IL-1b, IL-18), the major products of the NLRP3 inflammasome, remained unchanged. We then performed immunoblotting of the same NLRP3 inflammasome proteins in human atrial cardiomyocytes (HAM)-enriched fractions from patients with POAF, PAF and CAF. It was discovered that the NLRP3 inflammasome was strongly activated in the AF groups vs. the Ctl group with the POAF group showing the strongest activation. Our results position human atrial cardiomyocytes as a major source of inflammatory signaling and indicate that cardiomyocyte NLRP3-inflammasome signaling may contribute to the formation of the AF-promoting vulnerable substrate.


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