Exploring Electrospun Scaffold Innovations in Cardiovascular Therapy: A Review of Electrospinning in Cardiovascular Disease.

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide. In particular, patients who suffer from ischemic heart disease (IHD) that is not amenable to surgical or percutaneous revascularization techniques have limited treatment options. Furthermore, after revascularization is successfully implemented, there are a number of pathophysiological changes to the myocardium, including but not limited to ischemia-reperfusion injury, necrosis, altered inflammation, tissue remodeling, and dyskinetic wall motion. Electrospinning, a nanofiber scaffold fabrication technique, has recently emerged as an attractive option as a potential therapeutic platform for the treatment of cardiovascular disease. Electrospun scaffolds made of biocompatible materials have the ability to mimic the native extracellular matrix and are compatible with drug delivery. These inherent properties, combined with ease of customization and a low cost of production, have made electrospun scaffolds an active area of research for the treatment of cardiovascular disease. In this review, we aim to discuss the current state of electrospinning from the fundamentals of scaffold creation to the current role of electrospun materials as both bioengineered extracellular matrices and drug delivery vehicles in the treatment of CVD, with a special emphasis on the potential clinical applications in myocardial ischemia.

Crafting a Rigorous, Clinically Relevant Large Animal Model of Chronic Myocardial Ischemia: What Have We Learned in 20 Years?

The past several decades have borne witness to several breakthroughs and paradigm shifts within the field of cardiovascular medicine, but one component that has remained constant throughout this time is the need for accurate animal models for the refinement and elaboration of the hypotheses and therapies crucial to our capacity to combat human disease. Numerous sophisticated and high-throughput molecular strategies have emerged, including rational drug design and the multi-omics approaches that allow extensive characterization of the host response to disease states and their prospective resolutions, but these technologies all require grounding within a faithful representation of their clinical context. Over this period, our lab has exhaustively tested, progressively refined, and extensively contributed to cardiovascular discovery on the basis of one such faithful representation. It is the purpose of this paper to review our porcine model of chronic myocardial ischemia using ameroid constriction and the subsequent myriad of physiological and molecular-biological insights it has allowed our lab to attain and describe. We hope that, by depicting our methods and the insight they have yielded clearly and completely-drawing for this purpose on comprehensive videographic illustration-other research teams will be empowered to carry our work forward, drawing on our experience to refine their own investigations into the pathogenesis and eradication of cardiovascular disease.

The Current State of Extracellular Matrix Therapy for Ischemic Heart Disease.

The extracellular matrix (ECM) is a three-dimensional, acellular network of diverse structural and nonstructural proteins embedded within a gel-like ground substance composed of glycosaminoglycans and proteoglycans. The ECM serves numerous roles that vary according to the tissue in which it is situated. In the myocardium, the ECM acts as a collagen-based scaffold that mediates the transmission of contractile signals, provides means for paracrine signaling, and maintains nutritional and immunologic homeostasis. Given this spectrum, it is unsurprising that both the composition and role of the ECM has been found to be modulated in the context of cardiac pathology. Myocardial infarction (MI) provides a familiar example of this; the ECM changes in a way that is characteristic of the progressive phases of post-infarction healing. In recent years, this involvement in infarct pathophysiology has prompted a search for therapeutic targets: if ECM components facilitate healing, then their manipulation may accelerate recovery, or even reverse pre-existing damage. This possibility has been the subject of numerous efforts involving the integration of ECM-based therapies, either derived directly from biologic sources or bioengineered sources, into models of myocardial disease. In this paper, we provide a thorough review of the published literature on the use of the ECM as a novel therapy for ischemic heart disease, with a focus on biologically derived models, of both the whole ECM and the components thereof.

Immunosuppression and Neuroinflammation in Stroke Pathobiology.

Over the preceding decades, there have been substantial advances in our knowledge of the pathophysiology of stroke. One such advance has been an increased understanding of the multifarious crosstalk in which the nervous and immune systems engage in order to maintain homeostasis. By interrupting the immune-nervous nexus, it is thought that stroke induces change in both systems. Additionally, it has been found that both innate and adaptive immunosuppression play protective roles against the effects of stroke. The release of danger-/damage-associated molecular patterns (DAMPs) activates Toll-like receptors (TLRs), contributing to the harmful inflammatory effects of ischemia/reperfusion injury after stroke; the Tyro3, Axl, and MerTK (TAM)/Gas6 system, however, has been shown to suppress inflammation via downstream signaling molecules that inhibit TLR signaling. Anti-inflammatory cytokines have also been found to promote neuroprotection following stroke. Additionally, adaptive immunosuppression merits further consideration as a potential endogenous protective mechanism. In this review, we highlight recent studies regarding the effects and mechanism of immunosuppression on the pathophysiology of stroke, with the hope that a better understanding of the function of both of innate and adaptive immunity in this setting will facilitate the development of effective therapies for post-stroke inflammation.

Normobaric oxygen therapy attenuates hyperglycolysis in ischemic stroke.

Normobaric oxygen therapy has gained attention as a simple and convenient means of achieving neuroprotection against the pathogenic cascade initiated by acute ischemic stroke. The mechanisms underlying the neuroprotective efficacy of normobaric oxygen therapy, however, have not been fully elucidated. It is hypothesized that cerebral hyperglycolysis is involved in the neuroprotection of normobaric oxygen therapy against ischemic stroke. In this study, Sprague-Dawley rats were subjected to either 2-hour middle cerebral artery occlusion followed by 3- or 24-hour reperfusion or to a permanent middle cerebral artery occlusion event. At 2 hours after the onset of ischemia, all rats received either 95% oxygen normobaric oxygen therapy for 3 hours or room air. Compared with room air, normobaric oxygen therapy significantly reduced the infarct volume, neurological deficits, and reactive oxygen species and increased the production of adenosine triphosphate in ischemic rats. These changes were associated with reduced transcriptional and translational levels of the hyperglycolytic enzymes glucose transporter 1 and 3, phosphofructokinase 1, and lactate dehydrogenase. In addition, normobaric oxygen therapy significantly reduced adenosine monophosphate-activated protein kinase mRNA expression and phosphorylated adenosine monophosphate-activated protein kinase protein expression. These findings suggest that normobaric oxygen therapy can reduce hyperglycolysis through modulating the adenosine monophosphate-activated protein kinase signaling pathway and alleviating oxidative injury, thereby exhibiting neuroprotective effects in ischemic stroke. This study was approved by the Institutional Animal Investigation Committee of Capital Medical University (approval No. AEEI-2018-033) on August 13, 2018.

Beneficial effects of trimetazidine on expression of serotonin and serotonin transporter in rats with myocardial infarction and depression.

BACKGROUND: Trimetazidine is an anti-ischemic drug that can inhibit platelet aggregation and regulate serotonin (5-hydroxytryptamine [5-HT]) release. The purpose of this study was to investigate the therapeutic effects of trimetazidine on 5-HT and serotonin transporter (SERT) expression in experimentally induced myocardial infarction (MI), depression, and MI + depression. MATERIALS AND METHODS: Eighty Sprague Dawley (SD) rats were randomly divided into a trimetazidine group and a saline group of 40 rats each. The trimetazidine group was given trimetazidine pretreatment for 4 weeks, while the saline group received saline for 4 weeks. Both groups were then subdivided into four subgroups (n=10), which were each subjected to a unique disease condition: sham surgery, MI, depression, or MI + depression. All rats were sacrificed 3 days thereafter, and serum and platelet levels of 5-HT and SERT were assessed. In addition, we experimented with trimetazidine posttreatment. Twenty SD rats underwent MI surgery, and were then randomly divided into a treatment and a saline group (n=10 each). For 4 weeks post-surgery, the trimetazidine group was given trimetazidine, while the saline group received saline. Serum and platelet levels of 5-HT and SERT were assessed. RESULTS: Pretreatment with trimetazidine: in the nontreatment saline group, MI, depression, and MI + depression showed significant declines (P<0.05) in both serum and platelet 5-HT levels compared to sham. Trimetazidine treatment significantly increased serum and platelet 5-HT levels in the MI, depression, and MI + depression (P<0.05) subgroups compared to their counterparts in the saline group. Results for SERT were heterogeneous between serum and platelets. Trimetazidine treatment significantly decreased serum levels of SERT in the sham surgery subgroup (P<0.05), while significantly increasing levels in depression rats, compared to control (P<0.05). In platelets, trimetazidine significantly decreased SERT in sham surgery, MI, depression, and MI + depression rats, compared to control (P<0.05). This contrast suggests that trimetazidine has opposite effects in serum and platelet SERT levels for the three disease models. Post-surgery trimetazidine: increased serum 5-HT (P<0.05) and serum SERT (P<0.05) were observed, compared to control. In platelets, trimetazidine decreased both 5-HT and SERT compared to control, significantly (P<0.05) for 5-HT, but not significantly for SERT (P>0.05). CONCLUSION: Trimetazidine has a regulatory effect on 5-HT and SERT in the serum and platelets. Because of the downstream effects of this regulation on blood vessel function and myocardial protection, trimetazidine may be a therapeutic or preventive agent in several disease processes, including MI, depression, and the comorbidity between these two diseases. Further investigation, aimed at exploring the clinical potential of trimetazidine, is therefore warranted.

The cerebral circulation and cerebrovascular disease I: Anatomy.

In this paper, which is the first in a three-part series that reviews cerebrovascular anatomy, pathogenesis, and stroke, we lay the anatomical foundation for the rest of the series. Beginning with its origin in the branches of the aorta, we start by describing the arterial system. This system is partitioned into two major divisions (anterior and posterior circulations) that differ significantly in features and pathogenic potential. The systems, and the major branches that comprise them, are described. Description of the arterial system proceeds to the point of the fulfillment of its function. This function, the exchange of gases and nutrients with the cerebral parenchyma, is the subject of a subsequent section on the microcirculation and blood-brain barrier. Finally, the cerebral venous system, which is composed of cerebral veins and dural venous sinuses, is described. Thus, an anatomical context is supplied for the discussion of cerebrovascular disease pathogenesis provided by our second paper.

The cerebral circulation and cerebrovascular disease III: Stroke.

In this paper, our review series on cerebrovascular disease anatomy, physiology, and pathology ends with a thorough discussion of the most significant cerebrovascular pathology: stroke. This discussion proceeds through two layers of organization. First, stroke is divided up into its main etiologic categories (ischemic stroke/transient ischemic attack, hemorrhagic stroke, and ischemic to hemorrhagic transformation). Then, the epidemiological, pathophysiological, clinical, and therapeutic (employed currently as well as emerging) aspects of each etiology are explored; emphasis is placed upon the therapeutic aspects. Finally, once we have covered all aspects of each etiologic category, we end our review with a defense of the thesis that there is much hope for the future of stroke treatment to be derived from familiarity with the literature on emerging therapies.

The cerebral circulation and cerebrovascular disease II: Pathogenesis of cerebrovascular disease.

In this paper, we review the cerebral circulation and cerebrovascular disease (CVD) with an overview of the major types of CVD pathogenesis. These, as categorized here, are as follows: occlusive injury intrinsic to blood vessels, occlusive injury extrinsic to blood vessels, cerebral hypoperfusion, and cerebral hemorrhage. Following an overview of each of these categories, we conclude with a discussion of cerebral edema to illustrate how the pathological origins we covered can progress clinically. The content of this paper sets the stage for the detailed, clinically oriented discussion of stroke with which our series culminates in its subsequent Part III.