Anti‐inflammatory therapies in myocardial infarction: failures, hopes and challenges

Abstract

In the infarcted heart, the damage-associated molecular pattern proteins released by necrotic cells trigger both myocardial and systemic inflammatory responses. Induction of chemokines and cytokines and up-regulation of endothelial adhesion molecules mediate leukocyte recruitment in the infarcted myocardium. Inflammatory cells clear the infarct of dead cells and matrix debris and activate repair by myofibroblasts and vascular cells, but may also contribute to adverse fibrotic remodelling of viable segments, accentuate cardiomyocyte apoptosis and exert arrhythmogenic actions. Excessive, prolonged and dysregulated inflammation has been implicated in the pathogenesis of complications and may be involved in the development of heart failure following infarction. Studies in animal models of myocardial infarction (MI) have suggested the effectiveness of pharmacological interventions targeting the inflammatory response. This article provides a brief overview of the cell biology of the post-infarction inflammatory response and discusses the use of pharmacological interventions targeting inflammation following infarction. Therapy with broad anti-inflammatory and immunomodulatory agents may also inhibit important repair pathways, thus exerting detrimental actions in patients with MI. Extensive experimental evidence suggests that targeting specific inflammatory signals, such as the complement cascade, chemokines, cytokines, proteases, selectins and leukocyte integrins, may hold promise. However, clinical translation has proved challenging. Targeting IL-1 may benefit patients with exaggerated post-MI inflammatory responses following infarction, not only by attenuating adverse remodelling but also by stabilizing the atherosclerotic plaque and by inhibiting arrhythmia generation. Identification of the therapeutic window for specific interventions and pathophysiological stratification of MI patients using inflammatory biomarkers and imaging strategies are critical for optimal therapeutic design. Abbreviations11β-HSD, 11-β hydroxysteroid dehydrogenase;

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience

“…During this procedure, oxidative stress and endoplasmic reticulum stress also contribute to the cardiac injury [30,31]. The relationship between inflammation and cardiac arrest has been investigated extensively [32]. Adrie et al investigated the immuneinflammatory profile in cardiac arrest patients with successfully ROSC and found that high levels of plasma IL-6, IL-8, IL-10, and TNF receptor type II discriminated between survivors and non-survivors [33].…”

High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation

“…Based on the assumption that fibrosis is the result of a chronic, unsolved inflammation, the most exploited therapy so far has been the use of corticosteroids (8)(9)(10)(11)(12). However, it is now clear that therapy with antiinflammatory drugs does not provide objective benefit (13)(14)(15). Moreover, these drugs are associated with a myriad of adverse effects that eventually worsen patients' quality of life.…”

Glucocorticoid Receptor ablation promotes cardiac regeneration by hampering cardiomyocyte terminal differentiation

“…The possibility to interfere with inflammatory processes post-MI by the administration of glucocorticoids has been studied for a long time in the attempt to reduce fibrotic remodelling 55 . However, inflammation is also a required factor to achieve regeneration of multiple organs 56 , including the heart of neonatal mice following injury 57,58 .…”