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.

/pdf/the-biological-basis-for-cardiac-repair-after-myocardial-198isjzhg7.pdf

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

Platelets — blood cells continuously produced from megakaryocytes mainly in the bone marrow — are implicated not only in haemostasis and arterial thrombosis, but also in other physiological and pathophysiological processes. This Review describes current evidence for the heterogeneity in platelet structure, age, and activation properties, with consequences for a diversity of platelet functions. Signalling processes of platelet populations involved in thrombus formation with ongoing coagulation are well understood. Genetic approaches have provided information on multiple genes related to normal haemostasis, such as those encoding receptors and signalling or secretory proteins, that determine platelet count and/or responsiveness. As highly responsive and secretory cells, platelets can alter the environment through the release of growth factors, chemokines, coagulant factors, RNA species, and extracellular vesicles. Conversely, platelets will also adapt to their environment. In disease states, platelets can be positively primed to reach a pre-activated condition. At the inflamed vessel wall, platelets interact with leukocytes and the coagulation system, interactions mediating thromboinflammation. With current antiplatelet therapies invariably causing bleeding as an undesired adverse effect, novel therapies can be more beneficial if directed against specific platelet responses, populations, interactions, or priming conditions. On the basis of these novel concepts and processes, we discuss several initiatives to target platelets therapeutically. This Review provides an update of the latest developments in our understanding of platelet functions and populations in normal physiology and in haemorrhagic, thrombotic, and inflammatory conditions. These advancements can aid in tailoring new strategies to target platelets in disease states while avoiding the increased risk of bleeding associated with current antiplatelet therapies.

Platelet biology and functions: new concepts and clinical perspectives.

Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities.

Thrombosis is the most feared complication of cardiovascular diseases and a main cause of death worldwide, making it a major health-care challenge. Platelets and the coagulation cascade are effectively targeted by antithrombotic approaches, which carry an inherent risk of bleeding. Moreover, antithrombotics cannot completely prevent thrombotic events, implicating a therapeutic gap due to a third, not yet adequately addressed mechanism, namely inflammation. In this Review, we discuss how the synergy between inflammation and thrombosis drives thrombotic diseases. We focus on the huge potential of anti-inflammatory strategies to target cardiovascular pathologies. Findings in the past decade have uncovered a sophisticated connection between innate immunity, platelet activation and coagulation, termed immunothrombosis. Immunothrombosis is an important host defence mechanism to limit systemic spreading of pathogens through the bloodstream. However, the aberrant activation of immunothrombosis in cardiovascular diseases causes myocardial infarction, stroke and venous thromboembolism. The clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is supported by the increased risk of cardiovascular events in patients with inflammatory diseases but also during infections, including in COVID-19. Clinical trials in the past 4 years have confirmed the anti-ischaemic effects of anti-inflammatory strategies, backing the concept of a prothrombotic function of inflammation. Targeting inflammation to prevent thrombosis leaves haemostasis mainly unaffected, circumventing the risk of bleeding associated with current approaches. Considering the growing number of anti-inflammatory therapies, it is crucial to appreciate their potential in covering therapeutic gaps in cardiovascular diseases.

/pdf/interplay-between-inflammation-and-thrombosis-in-wx6by7s8is.pdf

Interplay between inflammation and thrombosis in cardiovascular pathology.

The selectins are transmembrane, Ca(2+)-dependent lectins that mediate leucocyte rolling on vascular surfaces, the first adhesive step during inflammation and immune surveillance. Leucocytes express L-selectin, activated platelets express P-selectin, and activated endothelial cells express E- and P-selectin. Rolling involves force-regulated, rapidly reversible interactions of selectins with a limited number of glycosylated cell surface ligands. Rolling permits leucocytes to interact with immobilized chemokines that convert β2 integrins to high-affinity conformations, which mediate arrest, post-arrest adhesion strengthening, and transendothelial migration. However, rolling leucocytes also transduce signals through selectin ligands, the focus of this review. These signals include serial activation of kinases and recruitment of adaptors that convert integrins to intermediate-affinity conformations, which decrease rolling velocities. In vitro, selectin signalling enables myeloid cells to respond to suboptimal levels of chemokines and other agonists. This cooperative signalling triggers effector responses such as degranulation, superoxide production, chemokine synthesis, and release of procoagulant/proinflammatory microparticles. In vivo, selectin-mediated adhesion and signalling likely contributes to atherosclerosis, arterial and deep vein thrombosis, ischaemia-reperfusion injury, and other cardiovascular diseases.

/pdf/selectins-initiators-of-leucocyte-adhesion-and-signalling-at-1iuertr41f.pdf

Selectins: initiators of leucocyte adhesion and signalling at the vascular wall.

Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non–ST-Segment Elevation Myocardial Infarction : Results of the SELECT-ACS Trial

The efficacy of COVID‐19 convalescent plasma (CCP) as a treatment for hospitalized patients with COVID‐19 remains somewhat controversial; however, many studies have not evaluated CCP documented to have high neutralizing antibody titer by a highly accurate assay. To evaluate the correlation of the administration of CCP with titer determined by a live viral neutralization assay with 7‐ and 28‐day death rates during hospitalization, a total of 23 118 patients receiving a single unit of CCP were stratified into two groups: those receiving high titer CCP (>250 50% inhibitory dilution, ID50; n = 13 636) or low titer CCP (≤250 ID50; n = 9482). Multivariable Cox regression was performed to assess risk factors. Non‐intubated patients who were transfused with high titer CCP showed 1.1% and 1.7% absolute reductions in overall 7‐ and 28‐day death rates, respectively, compared to those non‐intubated patients receiving low titer CCP. No benefit of CCP was observed in intubated patients. The relative benefit of high titer CCP was confirmed in multivariable Cox regression. Administration of CCP with high titer antibody content determined by live viral neutralization assay to non‐intubated patients is associated with modest clinical efficacy. Although shown to be only of modest clinical benefit, CCP may play a role in the future should viral variants develop that are not neutralized by other available therapeutics.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ajh.26531

Early administration of COVID‐19 convalescent plasma with high titer antibody content by live viral neutralization assay is associated with modest clinical efficacy

In the process of aligning treatment options to fit each individual patient, the clinician must carefully evaluate how each decision affects the overarching goals of care. In the management of coronary artery disease, however, these tradeoffs are often confounded by a bias toward less invasive strategies in the elderly. Given that women outnumber men by 54% beyond the age of 80 years,1 this predisposition can also contribute to an insidious form of gender discrimination. Older patients are often excluded from major clinical trials,2 contributing to a lack of awareness surrounding the efficacy of aggressive treatments in this demographic. 

Solving the Puzzle of Coronary Artery Disease in the Elderly.

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Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non–ST-Segment Elevation Myocardial Infarction : Results of the SELECT-ACS Trial

Early administration of COVID‐19 convalescent plasma with high titer antibody content by live viral neutralization assay is associated with modest clinical efficacy

Solving the Puzzle of Coronary Artery Disease in the Elderly.