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  • Overexpression of GCP has been linked to improved

    2019-07-06

    Overexpression of GCP-2 has been linked to improved LV remodeling by increasing pro-angiogenic and anti-apoptotic gene expression within the infarct [36]. Less is known about the role of lymphotactin (Xcl1) during the cardiac remodeling processes, in part due to conflicting results. In a rat model of cardiac allograft, lymphotactin was linked to accelerated allograft rejection [37]. In contrast, lymphotactin expression was not associated with rejection in cardiac allograft recipients [38]. Ccr8 is primarily expressed by regulatory T-cells and is known to regulate monocyte chemotaxis [39,40]. In left ventricular assist device patients, decreased Ccr8 expression was found to correlate with increased 1 year mortality [41]; however, its post-MI role has not been extensively studied. Multiple studies have shown negative [[42], [43], [44]] and positive [[45], [46], [47]] correlations between monocyte and macrophage numbers and MI LV remodeling. Macrophages regulate a number of wound healing events, including removal of cell debris, development of the infarct scar, and angiogenesis [2,21]. In a recent publication, we demonstrated that at day 1 post-MI, the macrophage exhibits a pro-inflammatory phenotype and by day 7 post-MI, macrophages exhibit a reparative phenotype that indirectly contributes to ECM formation through release of paracrine factors and directly secretes ECM proteins (collagen and periostin) [21]. Decreased day 7 reparative macrophages would exacerbate LV remodeling resulting in the extreme dilator phenotype. White blood cell count within 24 h of admission for an MI (inflammatory phase) is a strong and independent predictor of in-hospital and 30-day mortality as well as in-hospital clinical events [7]. Our data indicated that during the later maturation phase of wound healing, neutrophil numbers are not strong predictors for adverse remodeling. Neutrophils likely have an indicator role early during days 1–3 after MI during the phase that neutrophils are the prominent cell type. Macrophages become the primary cell at around post-MI day 5 making these 2-NBDG inhibitor ideal for predicting LV changes during the proliferative and maturation phase of cardiac wound healing. A strength of using the multimarker panel is that despite having overlap, each of the biomarkers regulate separate pathways of the LV remodeling process. For example, MIP-1γ regulates macrophage recruitment, while GCP-2 is a pro-angiogenic protein secreted by macrophages and lymphotactin and Ccr8 are markers of T-cell mediated inflammation [36,39,[48], [49], [50]]. Having biomarkers that incorporate multiple aspects of MI remodeling can improve specificity and sensitivity because they are not inter-dependent [51,52]. Another strength is that the plasma results alone provided a strong composite indicator, which improves ease of use and cost-effectiveness. Future evaluations to determine if these markers have translational relevance in clinical cohorts are warranted.
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    Introduction Aging is commonly defined as the functional decline over time in living organisms [1]. The incidence of cardiovascular diseases dramatically increases with age. Over time, heart and vasculature gradually become homeostatic imbalance; left ventricular wall thickening and vascular stiffening and fibrosis lead to accentuated tissue adaptations and decreased stress tolerance [2]. Increased cardiomyocyte death, proliferation of myocyte nuclei, increased cardiomyocyte volume, and accumulation of connective tissues often manifest in the myocardium of old animals [3]. Continuous efforts have been made to delineate underlying mechanisms and to seek therapeutic interventions for aging-related cardiac dysfunction. Emerging from these studies, mitochondria have been demonstrated a central role in age-related pathological alterations of the heart [1,[4], [5], [6]]. Mitochondria play important roles in a myriad of cellular processes including ATP production via oxidative phosphorylation, fatty acid oxidation, biosynthetic pathways, urea cycle, cellular redox homeostasis, ion homeostasis, oxygen sensing, calcium storage, and regulation of programmed cell death [7]. Because more than 90% of the large amount of ATP consumed by the homeostatic maintenance and contractile function of the heart are provided by mitochondria, the heart is particularly vulnerable to mitochondrial dysfunction [8,9]. Cardiac aging is often accompanied by a general decline in mitochondrial function, clonal expansion of dysfunctional mitochondria, increased production of reactive oxygen species (ROS), suppressed mitophagy, and dysregulation of mitochondrial quality control processes [[10], [11], [12]]. Accordingly, development of novel therapeutic approaches for the attenuation of mitochondrial insults and rejuvenation of mitochondrial collective holds promise for decreasing morbidity and mortality related to cardiac aging.