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Journal ArticleDOI

The inflammatory response in myocardial injury, repair, and remodelling.

25 Mar 2014-Nature Reviews Cardiology (Nature Publishing Group)-Vol. 11, Iss: 5, pp 255-265
TL;DR: Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies in patients with myocardial infarction.
Abstract: Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of postinfarction remodelling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited to the infarcted area, remove dead cells and matrix debris by phagocytosis, while preparing the area for scar formation. Timely repression of the inflammatory response is critical for effective healing, and is followed by activation of myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor β family are critically involved in suppression of inflammation and activation of a profibrotic programme. Translation of these concepts to the clinic requires an understanding of the pathophysiological complexity and heterogeneity of postinfarction remodelling in patients with myocardial infarction. Individuals with an overactive and prolonged postinfarction inflammatory response might exhibit left ventricular dilatation and systolic dysfunction and might benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with an exaggerated fibrogenic reaction can develop heart failure with preserved ejection fraction and might require inhibition of the Smad3 (mothers against decapentaplegic homolog 3) cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies.

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15 Aug 2013
TL;DR: This review discusses the pathogenesis and management of coronary microvascular dysfunction and factors to consider in clinical management are the cause of the dysfunction and whether it is iatrogenic, whether obstructive coronary artery disease is present, and whether myocardial disease ispresent.
Abstract: This review discusses the pathogenesis and management of coronary microvascular dysfunction. Factors to consider in clinical management are the cause of the dysfunction and whether it is iatrogenic, whether obstructive coronary artery disease is present, and whether myocardial disease is present.

1,299 citations

Journal ArticleDOI
TL;DR: The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts, and therapeutic modulation of the inflammatory and reparative response may hold promise for the prevention of postinfarction heart failure.
Abstract: In adult mammals, massive sudden loss of cardiomyocytes after infarction overwhelms the limited regenerative capacity of the myocardium, resulting in the formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of proinflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/ chemokine (C-C motif) ligand 2 [CCL2]). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin–angiotensin–aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response after myocardial infarction. Dysregulation of immune pathways, impaired suppression of postinfarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for the prevention of postinfarction heart failure.

1,266 citations


Cites background from "The inflammatory response in myocar..."

  • ...A study using cardiac magnetic resonance imaging in p50−/− mice demonstrated that leukocyte p50 expression imparts beneficial effects on remodeling after nonreperfused MI, by improving scar stability and matrix remodeling, and attenuating leukocyte infiltration and cytokine expression.106 These results contrasted with prior I/R and permanent ligation studies of p50−/− mice that reported the opposite results,107,108 but were consistent with a more recent study showing no effects of myocardial p50 deficiency on infarct size during ex vivo I/R in the isolated perfused heart when the influence of circulating leukocytes was removed.109 Taken together, although further study is clearly required, the prevailing evidence underscores the importance of subunitspecificity and cellular localization as determinants of NFκB–mediated responses after MI....

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  • ...As discussed in the text, cell-type–specific innate immune signaling can result in distinctive, and sometimes divergent, in vivo physiological responses during acute MI. Schema derived from Mann,13 Newton and Dixit,14 Schroder and Tschopp,18 Chao,76 and Mann83 (Illustration credit: Ben Smith). by guest on N ovem ber 1, 2017 http://circres.ahajournals.org/ D ow nloaded from TLR pathways) to active IL-18 and IL-1β (Figure 2)....

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  • ...Thus, growth differentiation factor-15 loss in mice is associated with accentuated postinfarction inflammation and fatal cardiac rupture after MI.202 In patients with ST-segment– elevation MI, elevated plasma growth differentiation factor-15 levels are associated with increased mortality,203 likely reflecting activation of a protective anti-inflammatory pathway in patients with an accentuated postinfarction inflammatory reaction....

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  • ...Interestingly, S100A1, the S100 protein most abundant in cardiomyocytes, is also released from damaged cardiomyocytes in both humans and mice with acute MI.48 However, rather than promoting generalized inflammation, S100A1 is taken up by endocytosis in adjacent cardiac fibroblasts to transiently activate TLR4-endolysosomal signaling, resulting in an immunomodulatory and antifibrotic phenotype with beneficial effects on post-MI LV remodeling in vivo.48 This suggests that specific DAMPs have unique cell targets and functional roles in the cardiac repair process that can be either pro- or anti-inflammatory....

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  • ...In this regard, a recent study has demonstrated that circulating IL-1β induces the proliferation of bone marrow hematopoietic stem cells after MI, thereby enhancing circulating leukocytes and inflammation in the infarcted heart.127 As another example, the chemokine CXCL12/stromal cell–derived factor-1 may facilitate cardiac repair after MI by promoting homing and survival of stem cells and neovascularization.128,129 Finally, it is important to recognize that the inflammation is a required event for effective tissue repair, and as such suppression of inflammatory activation that is not dysregulated or excessive may not necessarily result in salubrious effects on cardiac remodeling after MI....

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Journal ArticleDOI
TL;DR: In this article, the intrinsic biochemical properties of reactive oxygen species (ROS) underlie the mechanisms that regulate various physiological functions of living organisms, and they play an essential role in regulating various physiological function.
Abstract: Reactive oxygen species (ROS) play an essential role in regulating various physiological functions of living organisms. The intrinsic biochemical properties of ROS, which underlie the mechanisms ne...

1,260 citations

Journal ArticleDOI
TL;DR: Understanding the complex pathophysiological processes and dynamic changes of AF-associated inflammation might help to identify specific anti-inflammatory strategies for the prevention of AF.
Abstract: Atrial fibrillation (AF) is the most common cardiac arrhythmia. However, the development of preventative therapies for AF has been disappointing. The infiltration of immune cells and proteins that mediate the inflammatory response in cardiac tissue and circulatory processes is associated with AF. Furthermore, the presence of inflammation in the heart or systemic circulation can predict the onset of AF and recurrence in the general population, as well as in patients after cardiac surgery, cardioversion, and catheter ablation. Mediators of the inflammatory response can alter atrial electrophysiology and structural substrates, thereby leading to increased vulnerability to AF. Inflammation also modulates calcium homeostasis and connexins, which are associated with triggers of AF and heterogeneous atrial conduction. Myolysis, cardiomyocyte apoptosis, and the activation of fibrotic pathways via fibroblasts, transforming growth factor-β and matrix metalloproteases are also mediated by inflammatory pathways, which can all contribute to structural remodelling of the atria. The development of thromboembolism, a detrimental complication of AF, is also associated with inflammatory activity. Understanding the complex pathophysiological processes and dynamic changes of AF-associated inflammation might help to identify specific anti-inflammatory strategies for the prevention of AF.

634 citations

Journal ArticleDOI
TL;DR: A phase IIb study conducted among diabetic patients at high vascular risk indicates that canakinumab, a human monoclonal antibody that targets IL-1β, markedly reduces plasma levels of IL-6, hsCRP, and fibrinogen with little change in atherogenic lipids.
Abstract: Plasma levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) predict vascular risk with an effect estimate as large as that of total or high-density lipoprotein cholesterol. Further, randomized trial data addressing hsCRP have been central to understanding the anti-inflammatory effects of statin therapy and have consistently demonstrated on-treatment hsCRP levels to be as powerful a predictor of residual cardiovascular risk as on-treatment levels of low-density lipoprotein cholesterol. Yet, although hsCRP is clinically useful as a biomarker for risk prediction, most mechanistic studies suggest that CRP itself is unlikely to be a target for intervention. Moving upstream in the inflammatory cascade from CRP to interleukin (IL)-6 to IL-1 provides novel therapeutic opportunities for atheroprotection that focus on the central IL-6 signaling system and ultimately on inhibition of the IL-1β-producing NOD-like receptor family pyrin domain containing 3 inflammasome. Cholesterol crystals, neutrophil extracellular traps, atheroprone flow, and local tissue hypoxia activate the NOD-like receptor family pyrin domain containing 3 inflammasome. As such, a unifying concept of hsCRP as a downstream surrogate biomarker for upstream IL-1β activity has emerged. From a therapeutic perspective, small ischemia studies show reductions in acute-phase hsCRP production with the IL-1 receptor antagonist anakinra and the IL-6 receptor blocker tocilizumab. A phase IIb study conducted among diabetic patients at high vascular risk indicates that canakinumab, a human monoclonal antibody that targets IL-1β, markedly reduces plasma levels of IL-6, hsCRP, and fibrinogen with little change in atherogenic lipids. Canakinumab in now being tested as a method to prevent recurrent cardiovascular events in a randomized trial of 10 065 post-myocardial infarction patients with elevated hsCRP that is fully enrolled and due to complete in 2017. Clinical trials using alternative anti-inflammatory agents active against the CRP/IL-6/IL-1 axis, including low-dose methotrexate and colchicine, are being explored. If successful, these trials will close the loop on the inflammatory hypothesis of atherosclerosis and serve as examples of how fundamental biologic principles can be translated into personalized medical practice.

604 citations

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Journal ArticleDOI
TL;DR: Left ventricular end-diastolic and end-systolic volume and ejection fraction data provide support for the beneficial effects of therapeutic agents such as angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking agents on the remodeling process.

2,215 citations