Evidence of Failed Resolution Mechanisms in Arrhythmogenic Inflammation, Fibrosis and Right Heart Disease

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  Figure 7. The central role of unresolved fibroblasts-associated inflammatory status in the development of arrhythmogenic cardiac fibrosis. During acute inflammation, the initiation of inflammation is normally followed by a resolution, in order to promote homeostasis. Failure in the activation of pro-resolving signals contributes to the exacerbation of cardiac cells’ release of proinflammatory stimuli. FB are highly sensitive to inflammatory agents. When activated, cardiac FB participate in increasing the production of inflammatory compounds, leading to the development of fibrosis, myocardial dysfunction and arrhythmogenicity.

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  Figure 1. Biomolecular orchestration of cellular events from cardiac insult to resolution opposed to persistent arrhythmogenic inflammation. Longstanding exposure of the atrium to myocardial injuries, infections or chronic pressure and dilation provokes the normal initiation of acute inflammation. In cardiomyocytes (CM), intracellular inflammatory response involves CamKII, NF-kB or NLRP3 inflammasome pathways activation, which contribute to CM deregulation of structural genes (Myh7), and secretion of proinflammatory cytokines including interleukins (IL-1β, IL-18) and chemokines (CXCL, CCL), leading to promotion of proinflammatory (M1)-macrophage infiltration. Proinflammatory signals contribute to the activation of cardiac fibroblasts (FB). FB activate additional pro-inflammatory signals (TGFβ, TNFα, PDGF) provoking FB differentiation into myo-FB, aiming to promote repair and wound healing, if the resolution signals are properly activated in response to inflammation initiation. Resolution mediators, including IL-10, LXA4, D- and E-series resolvins, contribute to terminate M1-macrophages infiltration, facilitate anti-inflammatory (M2)-macrophages polarization and phagocytosis, while…

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  Figure 2. Arachidonic acid-derived lipid mediators. Arachidonic acid (AA) interaction with COX1, COX2, 5LOX, 12LOX, or CYP450 enzymes mainly leads to the production of proinflammatory lipid mediators including leukotrienes, thromboxanes, and prostaglandins. AA interaction with COX1/2 or 15LOX can generate pro-resolution mediators including PDG2, LXA4, and LXB4.

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  Figure 3. Eicosapentaenoic acid-, and docosahexaenoic acid-derived lipid mediators Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compete with AA in interacting with COX1/2, 5LOX, 12LOX, and 15LOX. Lipids produced from EPA and DHA metabolism include E-series resolvins (RvE1-3) and D-series resolvins (RvD1-6), respectively, which are involved in pro-resolution mechanisms.

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  Figure 4. Categorization of inflammation- and resolution-promoting agents. In response to pathogens or injury stimuli (PAMPs, DAMPs), phospholipase A2 (PLA2)-induced biosynthesis of arachidonic acid (AA) leads to the production of proinflammatory lipid mediators including thromboxanes, leukotrienes, and prostaglandins. Such events mark the initiation phase of acute inflammation characterized by PMN chemotaxis, pro-inflammatory-[M1]-macrophages recruitment, and enhanced proinflammatory signals (NLRP3 inflammasome, NF-κB, IL-1β, CXCL1/2). Phagocytic M1-macrophages release 12/15 LOX, which promotes the activation of lipid-mediators (LM) class switching, where AA, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) interact with 12LOX and 15LOX enzymes to be metabolized into specialized pro-resolving mediators (SPMs) including PGD2 from AA, D-series resolvins from DHA, or E-series resolvins from EPA. SPMs promote anti-inflammatory (M2)-macrophage recruitment, inhibition of proinflammatory cytokines’ secretion, termination of inflammation, and regeneration of optimal functions. When the resolution mechanisms fail to occur, inflammation is perpetuated. Inflammatory mediators are…

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  Figure 5. FRM-induced arrhythmogenic channelopathy in cardiac myocytes. In the myocardium, failed resolution mechanisms are associated with increased infiltration of polymophonuclear leukocytes (PMN), enhanced M1-macrophages phagocytic activity and augmentation of the secretion of proinflammatory cytokines. Persistence of proinflammatory signals provokes deregulation of gene coding for key ion-channels and connexins involved in the establishment of cardiac action potential (AP) and conduction velocity. Inflammation-associated channelopathy induces: abnormal calcium-(Ca2+)-handling, effective refractory period (ERP) shortening, reduced AP duration (APD), slowed conduction, vulnerability to re-entry, and triggered activity leading to increased risk of cardiac arrhythmias and fibrillation.

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  Figure 6. Cardiomyocytes and Fibroblasts’ orchestration of arrhythmogenic extracellular matrix degradation. During acute inflammation, failure in the occurrence of resolution mechanisms (FRM) promotes exacerbation of inflammatory signals generated from apoptotic cardiac cells and activated cardiac FB, leading to an aggravation of myocardial damages. The extracellular matrix (ECM) is intensively remodeled and degraded, promoting a persistence of fibrosis, scar formation, abnormal cardiac function, and increased risk of arrhythmias, including AF.