Coronavirus disease 2019 (COVID‐19), the worst pandemic in more than a century, has claimed >125,000 lives worldwide to date. Emerging predictors for poor outcomes include advanced age, male sex, ...preexisting cardiovascular disease, and risk factors including hypertension, diabetes, and, more recently, obesity. This article posits new obesity‐driven predictors of poor COVID‐19 outcomes, over and above the more obvious extant risks associated with obesity, including cardiometabolic disease and hypoventilation syndrome in intensive care patients. This article also outlines a theoretical mechanistic framework whereby adipose tissue in individuals with obesity may act as a reservoir for more extensive viral spread, with increased shedding, immune activation, and cytokine amplification. This paper proposes studies to test this reservoir concept with a focus on specific cytokine pathways that might be amplified in individuals with obesity and COVID‐19. Finally, this paper underscores emerging therapeutic strategies that might benefit subsets of patients in which cytokine amplification is excessive and potentially fatal.
The heart hosts tissue resident macrophages which are capable of modulating cardiac inflammation and function by multiple mechanisms. At present, the consequences of phenotypic diversity in ...macrophages in the heart are incompletely understood. The contribution of cardiac M2-polarized macrophages to the resolution of inflammation and repair response following myocardial infarction remains to be fully defined. In this study, the role of M2 macrophages was investigated utilising a specific CSF-1 receptor signalling inhibition strategy to achieve their depletion. In mice, oral administration of GW2580, a CSF-1R kinase inhibitor, induced significant decreases in Gr1lo and F4/80hi monocyte populations in the circulation and the spleen. GW2580 administration also induced a significant depletion of M2 macrophages in the heart after 1 week treatment as well as a reduction of cardiac arginase1 and CD206 gene expression indicative of M2 macrophage activity. In a murine myocardial infarction model, reduced M2 macrophage content was associated with increased M1-related gene expression (IL-6 and IL-1β), and decreased M2-related gene expression (Arginase1 and CD206) in the heart of GW2580-treated animals versus vehicle-treated controls. M2 depletion was also associated with a loss in left ventricular contractile function, infarct enlargement, decreased collagen staining and increased inflammatory cell infiltration into the infarct zone, specifically neutrophils and M1 macrophages. Taken together, these data indicate that CSF-1R signalling is critical for maintaining cardiac tissue resident M2-polarized macrophage population, which is required for the resolution of inflammation post myocardial infarction and, in turn, for preservation of ventricular function.
Mesenchymal stromal cells (MSC) have immunomodulatory effects impacting macrophages, promoting polarisation towards a reparative phenotype. CCL2 is a potent cytokine involved in the recruitment of ...macrophages. We hypothesised that MSC derived CCL2 may be involved in the MSC therapeutic effect by facilitating macrophage repolarisation. To further delineate this mechanism, MSC isolated from CCL2 deficient mice (MSC-KO) were applied to excisional wounds in wild-type (WT) mice. CCL2 deficiency in MSC completely abrogated the therapeutic response compared to MSC-WT. MSC-KO were unable to repolarise macrophages to the same extent as WT and this was accompanied by a reduced angiogenesis and re-epithelialisation of the wounds at day 10. This study demonstrates that MSC derived CCL2 is required for MSC induced accelerated wound healing. The role of CCL2 in the interaction between MSC and Macrophages has not been previously demonstrated in accelerated wound healing. CCL2 has a potent effect on the ability to reduce the inflammatory response through local recruitment of macrophages. This research highlights CCL2 as a possible target for augmentation of MSC therapy to enhance therapeutic potential.
The field of vascular biology has been stimulated by the concept that circulating endothelial progenitor cells (EPCs) may play a role in neoangiogenesis (postnatal vasculogenesis). One problem for ...the field has been the difficulty in accurately defining an EPC. Likewise, circulating endothelial cells (CECs) are not well defined. The lack of a detailed understanding of the proliferative potential of EPCs and CECs has contributed to the controversy in identifying these cells and understanding their biology in vitro or in vivo. A novel paradigm using proliferative potential as one defining aspect of EPC biology suggests that a hierarchy of EPCs exists in human blood and blood vessels. The potential implications of this view in relation to current EPC definitions are discussed.
While basic and clinical research over the last several decades has recognized a number of modifiable risk factors associated with cardiometabolic disease progression, additional and alternative ...biological perspectives may offer novel targets for prevention and treatment of this disease set. There is mounting preclinical and emerging clinical evidence indicating that the mass of metabolically diverse microorganisms which inhabit the human gastrointestinal tract may be implicated in initiation and modulation of cardiovascular and metabolic disease outcomes. The following review will discuss this gut microbiome-host metabolism axis and address newly proposed bile-mediated signaling pathways through which dysregulation of this homeostatic axis may influence host cardiovascular risk. With a central focus on the major nuclear and membrane-bound bile acid receptor ligands, we aim to review the putative impact of microbial bile acid modification on several major phenotypes of metabolic syndrome, from obesity to heart failure. Finally, attempting to synthesize several separate but complementary hypotheses, we will review current directions in preclinical and clinical investigation in this evolving field.
Mesenchymal stem cells (MSCs) are currently under investigation as tools to preserve cardiac structure and function following acute myocardial infarction (AMI). However, concerns have emerged ...regarding safety of acute intracoronary (IC) MSC delivery. This study aimed to characterize innate prothrombotic activity of MSC and identify means of its mitigation toward safe and efficacious therapeutic IC MSC delivery post-AMI. Expression of the initiator of the coagulation cascade tissue factor (TF) on MSC was detected and quantified by immunofluorescence, FACS, and immunoblotting. MSC-derived TF antigen was catalytically active and capable of supporting thrombin generation in vitro. Addition of MSCs to whole citrated blood enhanced platelet thrombus deposition on collagen at arterial shear, an effect abolished by heparin coadministration. In a porcine AMI model, IC infusion of 25 × 10(6) MSC during reperfusion was associated with a decrease in coronary flow reserve but not when coadministered with an antithrombin agent (heparin). Heparin reduced MSC-associated thrombosis incorporating platelets and VWF within the microvasculature. Heparin-assisted therapeutic MSC delivery also reduced apoptosis in the infarct border zone at 24 hours, significantly improved infarct size, left ventricular (LV) ejection fraction, LV volumes, wall motion, and attenuated histologic evidence of scar formation at 6 weeks post-AMI. Heparin alone or heparin-assisted fibroblast control cell delivery had no such effect. Procoagulant TF activity of therapeutic MSCs is associated with reductions in myocardial perfusion when delivered IC may be successfully managed by heparin coadministration. This study highlights an important mechanistic insight into safety concerns associated with therapeutic IC MSC delivery for AMI.
Cell therapy to treat vascular and cardiovascular diseases has evolved over the past decade with improved understanding of progenitor cell mobilization, recruitment, and differentiation. The ...beneficial effects seen in several preclinical studies have prompted translation of adult vascular progenitor therapy to clinical trials. To date, progenitor cells isolated from bone marrow and peripheral blood have been tested in the context of acute myocardial infarction and chronic ischemic cardiomyopathy, with moderate benefit. This therapeutic effect occurs despite a relatively small number of injected progenitor cells and short-term residence in the target zone. Thus, indirect benefits, such as paracrine factors released from these cells, have been suggested as significant contributors to therapeutic efficacy. Several additional vascular progenitors of endothelial, smooth muscle, mesenchymal, and cardiac origin have been identified that may contribute to vasculogenesis. Indeed, a unifying paradigm for the most effective cell therapy strategies to date appears to be robust support of angiogenesis. Here we discuss a number of progenitor cells that currently show potential as cardiovascular therapeutics, either singly or in combination. We look at emerging cell types and disease targets that may be exploited for therapeutic benefit and future strategies that may maximize clinical efficacy.
This review aims to describe and compare porcine models of metabolic syndrome. This syndrome and its associated secondary comorbidities are set to become the greatest challenge to healthcare ...providers and policy makers in the coming century. However, an incomplete understanding of the pathogenesis has left significant knowledge gaps in terms of efficacious therapeutics. To further our comprehension and, in turn, management of metabolic syndrome, appropriate high-fidelity models of the disease complex are of great importance. In this context, our review aims to assess the most promising porcine models of metabolic syndrome currently available for their similarity to the human phenotype. In addition, we aim to highlight the strengths and shortcomings of each model in an attempt to identify the most appropriate application of each. Although no porcine model perfectly recapitulates the human metabolic syndrome, several pose satisfactory approximations. The Ossabaw miniature swine in particular represents a highly translatable model that develops each of the core parameters of the syndrome with many of the associated secondary comorbidities. Future high-fidelity porcine models of metabolic syndrome need to focus on secondary sequelae replication, which may require extended induction period to reveal.
COVID-19—Where Have All the STEMIs Gone? Tanner, Richard; MacDaragh Ryan, Paul; Caplice, Noel M.
Canadian journal of cardiology,
07/2020, Letnik:
36, Številka:
7
Journal Article
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