Sustained Ischemia Research Articles

Photo-Crosslinked Pro-Angiogenic Hydrogel Dressing for Wound Healing.

Severe burns are one of the most devastating injuries, in which sustained inflammation and ischemia often delay the healing process. Pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF) have been widely studied for promoting wound healing. However, the short half-life and instability of VEGF limit its clinical applications. In this study, we develop a photo-crosslinked hydrogel wound dressing from methacrylate hyaluronic acid (MeHA) bonded with a pro-angiogenic prominin-1-binding peptide (PR1P). The materials were extruded in wound bed and in situ formed a wound dressing via exposure to short-time ultraviolet radiation. The study shows that the PR1P-bonded hydrogel significantly improves VEGF recruitment, tubular formation, and cell migration in vitro. Swelling, Scanning Electron Microscope, and mechanical tests indicate the peptide does not affect the overall mechanical and physical properties of the hydrogels. For in vivo studies, the PR1P-bonded hydrogel dressing enhances neovascularization and accelerates wound closure in both deep second-degree burn and full-thickness excisional wound models. The Western blot assay shows such benefits can be related to the activation of the VEGF-Akt signaling pathway. These results suggest this photo-crosslinked hydrogel dressing efficiently promotes VEGF recruitment and angiogenesis in skin regeneration, indicating its potential for clinical applications in wound healing.

Mechanisms of Atherosclerotic Plaque Instability

Cardiovascular disease (CVD) is the leading cause of mortality in humans worldwide. The main cause of CVD is the formation of thrombi due to by unstable atherosclerotic plaque rupture on the arterial wall. Long-term accumulation of thrombi results in vascular remodeling, and subsequent-stenosis of the lumen obstructs the blood flow, thereby leading to myocardial tissue ischemia and hypoxia. Sustained ischemia and hypoxia lead to myocyte necrosis, resulting in irreversible myocardial injury. Many molecular and cellular mechanisms are associated with atherosclerotic plaque instability (API). For example, macrophages can produce various inflammatory factors, adhesion factors, chemokines and matrix metalloproteinases (MMPs), which play important roles in the pathophysiological mechanisms of API and in maintaining plaque stability. These molecules may help predict unstable atherosclerotic plaques. If the plaque is stable, it will not be prone to rupture or thrombosis. Accordingly, in this review, we will discuss the different pathophysiological mechanisms of API and the related roles of macrophages in the mechanisms of API mainly in animal models and humans. We believe this review will provide a theoretical basis for the development of treatments and diagnostic approaches for the management of API.

Non-neuronal acetylcholine is causal for cardioprotection by hypoxic preconditioning in adult rat cardiomyocytes

Abstract Introduction Brief episodes of non-lethal myocardial ischemia/reperfusion preceding more sustained ischemia and reperfusion reduce lethal ischemia/reperfusion injury. The underlying protective signaling mechanisms of such ischemic preconditioning are unclear in their details. Among other protective mediators, neuronal acetylcholine (ACh) and its signaling through cholinergic receptors is involved in protection by ischemic preconditioning. Recently, a non-neuronal cardiac cholinergic system (NNCCS) has been identified, suggesting that a nervous system-independent, cardiomyocyte-derived acetylcholine signaling with signal amplification by auto- and paracrine cholinergic receptor activation could also participate in ischemic preconditioning. Aim We aimed to examine the role of NNCCS-derived ACh as a mediator of ischemic preconditioning. We therefore, in a reductionist approach, used isolated adult cardiomyocytes with hypoxic preconditioning (HPC). Methods Adult ventricular rat cardiomyocytes were isolated (from n=9 hearts), and HPC was induced by one cycle of 10 min hypoxia / 20 min reoxygenation. Thirty min normoxia served as control. Cardiomyocytes were then exposed to 30 min sustained hypoxia / 5 min reoxygenation (H/R), or a 35 min time control (TC). Cardiomyocyte viability was quantified before and after H/R or TC, respectively, by trypan blue staining. In a subgroup of experiments (cardiomyocytes from n=6 hearts) in the presence of physostigmine (0.2 mmol/L), intracellular ACh was quantified before and after HPC or normoxia and after sustained hypoxia and reoxygenation or TC, respectively, via liquid chromatography-coupled tandem mass spectrometry. Experiments on cardiomyocyte viability (from n=9 hearts) were repeated with the addition of cholinergic receptor antagonists (nicotinic: hexamethonium [1 µmol/L], muscarinic: atropine [0.1 µmol/L]) a) during the first 30 min with HPC or normoxia, b) during H/R or TC (30-65 min), or c) throughout the total 65 min protocol. Results The viability of cardiomyocytes subjected to H/R was better preserved with HPC than without (Figure A), and intracellular ACh was increased during hypoxia after prior HPC (Figure B). Cholinergic receptor antagonists during HPC did not change HPC´s protection (Figure A). However, the combination of both antagonists during sustained hypoxia abrogated HPC´s protection (Figure A), whereas nicotinic or muscarinic cholinergic receptor antagonists alone did not. Cholinergic receptor antagonists throughout the total 65 min also abrogated HPC´s protection (Figure A). Conclusion: The NNCCS is activated by HPC and causal for HPC´s protection. HPC increases intracellular acetylcholine, and cardiomyocyte protection is mediated via both nicotinic and muscarinic cholinergic receptors, suggesting an auto- and paracrine signal amplification on the cardiomyocyte level.Figure

Abstract 13423: Magnetocardiography as a Noninvasive Diagnostic Strategy for Ischemia Evaluating Following Coronary Revascularization of Patients With Non-ST Segment Elevation Myocardial Infarction

Introduction: Magnetocardiography (MCG) constitutes a non-invasive and radiation-free procedure that quantifies the heart's magnetic fields and has exhibited sensitive diagnostic capabilities for ischemia. Typically, MCG presents a distinctive pattern in healthy subjects, characterized by a positive and a negative pole that forms an angle of approximately 45-60 degrees within the T peak segment. Hypothesis: Our study aims to monitor the significant alterations in MCG patterns among patients with Non-ST Segment Elevation Myocardial Infarction (NSTEMI) undergoing revascularization. Methods: Patients were prospectively enrolled and MCG scans were conducted thrice: three days pre-intervention, one week post-intervention, and at a three-month follow-up. Results: Four patients underwent anatomical complete revascularization, while one patient had incomplete revascularization. When comparing the MCG patterns of patients with NSTEMI (Figures B-F) to a normal MCG pattern (Figure A), pre-intervention scans showed angular deflection (80%, except for patient 3) and an anomalous distribution of poles (100%). One week post-intervention, patients who underwent complete revascularization (Figures B-D) had myocardial enzymes normalized, along with slight angle recovery and reshaping of the poles (100%). By the three-month follow-up, these patients experienced symptom resolution, and their MCG patterns showed normalized angles with recovered poles (100%). However, the patient who underwent incomplete revascularization (Figure F) exhibited sustained myocardial ischemia symptoms, with no further angle recovery and continued anomalous distribution of positive poles, both post-intervention and during follow-up. Conclusions: The distribution of poles and angular deflection could potentially serve as indicators of ischemia. MCG may represent a promising strategy for evaluating myocardial recovery in patients with NSTEMI.

Robust critical limb ischemia porcine model involving skeletal muscle necrosis

This work sought to develop a robust and clinically relevant swine model of critical limb ischemia (CLI) involving the onset of ischemic muscle necrosis. CLI carries about 25–40% risk of major amputation with 20% annual mortality. Currently, there is no specific treatment that targets the ischemic myopathy characteristic of CLI. Current swine models of CLI, with tolerable side-effects, fail to achieve sustained ischemia followed by a necrotic myopathic endpoint. Such limitation in experimental model hinders development of effective interventions. CLI was induced unilaterally by ligation-excision of one inch of the common femoral artery (CFA) via infra-inguinal minimal incision in female Yorkshire pigs (n = 5). X-ray arteriography was done pre- and post-CFA transection to validate successful induction of severe ischemia. Weekly assessment of the sequalae of ischemia on limb perfusion, and degree of ischemic myopathy was conducted for 1 month using X-ray arteriography, laser speckle imaging, CTA angiography, femoral artery duplex, high resolution ultrasound and histopathological analysis. The non-invasive tissue analysis of the elastography images showed specific and characteristic pattern of increased muscle stiffness indicative of the fibrotic and necrotic outcome expected with associated total muscle ischemia. The prominent onset of skeletal muscle necrosis was evident upon direct inspection of the affected tissues. Ischemic myopathic changes associated with inflammatory infiltrates and deficient blood vessels were objectively validated. A translational model of severe hindlimb ischemia causing ischemic myopathy was successfully established adopting an approach that enables long-term survival studies in compliance with regulatory requirements pertaining to animal welfare.

Outcome of Out-of-Hospital Cardiac Arrest Patients Stratified by Pre-Clinical Loading with Aspirin and Heparin: A Retrospective Cohort Analysis.

Background: Out-of-hospital cardiac arrest (OHCA) has a high prevalence of obstructive coronary artery disease and total coronary occlusion. Consequently, these patients are frequently loaded with antiplatelets and anticoagulants before hospital arrival. However, OHCA patients have multiple non-cardiac causes and high susceptibility for bleeding. In brief, there is a gap in the evidence for loading in OHCA patients. Objective: The current analysis stratified the outcome of patients with OHCA according to pre-clinical loading. Material and Methods: In a retrospective analysis of an all-comer OHCA registry, patients were stratified by loading with aspirin (ASA) and unfractionated heparin (UFH). Bleeding rate, survival to hospital discharge and favorable neurological outcomes were measured. Results: Overall, 272 patients were included, of whom 142 were loaded. Acute coronary syndrome was diagnosed in 103 patients. One-third of STEMIs were not loaded. Conversely, 54% with OHCA from non-ischemic causes were pretreated. Loading was associated with increased survival to hospital discharge (56.3 vs. 40.3%, p = 0.008) and a more favorable neurological outcome (80.7 vs. 62.6% p = 0.003). Prevalence of bleeding was comparable (26.8 vs. 31.5%, p = 0.740). Conclusions: Pre-clinical loading did not increase bleeding rates and was associated with favorable survival. Overtreatment of OHCA with non-ischemic origin, but also undertreatment of STEMI-OHCA were documented. Loading without definite diagnosis of sustained ischemia is debatable in the absence of reliable randomized controlled data.

Effects of Iron Nanoparticles Administration on Ischemia/Reperfusion Injury in Isolated Hearts of Male Wistar Rats.

Iron is an essential mineral participating in numerous biological processes in the organism under physiological conditions. However, it may be also involved in the pathological mechanisms activated in various cardiovascular diseases including myocardial ischemia/reperfusion (I/R) injury, due to its involvement in reactive oxygen species (ROS) production. Furthermore, iron has been reported to participate in the mechanisms of iron-dependent cell death defined as "ferroptosis". On the other hand, iron may be also involved in the adaptive processes of ischemic preconditioning (IPC). This study aimed to elucidate whether small amounts of iron may modify the cardiac response to I/R in isolated perfused rat hearts and their protection by IPC. Pretreatment of the hearts with iron nanoparticles 15 min prior to sustained ischemia (iron preconditioning, Fe-PC) did not attenuate post-I/R contractile dysfunction. Recovery of left ventricular developed pressure (LVDP) was significantly improved only in the group with combined pretreatment with iron and IPC. Similarly, the rates of contraction and relaxation [+/-(dP/dt)max] were almost completely restored in the group preconditioned with a combination of iron and IPC but not with iron alone. In addition, the severity of reperfusion arrhythmias was reduced only in the iron+IPC group. No changes in protein levels of "survival" kinases of the RISK pathway (Reperfusion Injury Salvage Kinase) were found except for reduced caspase 3 levels in both preconditioned groups. The results indicate that a failure to precondition rat hearts with iron may be associated with the absent upregulation of RISK proteins and the pro-ferroptotic effect manifested by reduced glutathione peroxidase 4 (GPX4) levels. However, combination with IPC suppressed the negative effects of iron resulting in cardioprotection.

Beta 3-Adrenergic Receptor (?3-AR) Activation at the End of Sustained Ischemia and/or Early Reperfusion may Prove to be a Valuable Cardioprotective Strategy

The contribution of ?3-AR activation towards ischemiareperfusion (IR) damage largely depends on the disease stage, severity, experimental model as well as drug specificities which should be considered when investigating ?3-AR pharmacology for potential therapeutic applications.

Treatment-resistant diabetic chorea manifesting with psychiatric symptoms: a case report

ABSTRACT We report a case of a 69-year-old man with treatment-resistant diabetic chorea presenting psychiatric symptoms. The right chorea lasted for 3 months and was refractory to control of diabetes mellitus or administration of haloperidol and benzodiazepines. Only administration of tiapride was efficacious. Magnetic resonance spectrometry and dopamine transporter-single photon emission computed tomography suggested that sustained ischemia at the striatum may lead to impaired expression of dopamine transporters, thereby resulting in deterioration in the indirect pathway. Tiapride inhibited dopamine D2 receptors, thereby restoring the function of the indirect pathway and resulting in improvement of diabetic chorea.

Role of coagulation in persistent renal ischemia following reperfusion in an animal model.

Ischemic acute kidney injury is common, deadly, and accelerates the progression of chronic kidney disease, yet has no specific therapy. After ischemia, reperfusion is patchy with early and persistent impairment in regional renal blood flow and cellular injury. We tested the hypothesis that intrarenal coagulation results in sustained renal ischemia following reperfusion, using a well-characterized model. Markedly decreased, but heterogeneous, microvascular plasma flow with microthrombi was found postischemia by intravital microscopy. Widespread tissue factor expression and fibrin deposition were also apparent. Clotting was accompanied by complement activation and inflammation. Treatment with exosomes derived from renal tubular cells or with the fibrinolytic urokinase, given 24 h postischemia when renal failure was established, significantly improved microvascular flow, coagulation, serum creatinine, and histological evidence of injury. These data support the hypothesis that intrarenal clotting occurs early and the resultant sustained ischemia is a critical determinant of renal failure following ischemia; they demonstrate that the coagulation abnormalities are amenable to therapy and that therapy results in improvement in both function and postischemic inflammation.NEW & NOTEWORTHY Ischemic renal injury carries very high morbidity and mortality, yet has no specific therapy. We found markedly decreased, heterogeneous microvascular plasma flow, tissue factor induction, fibrin deposition, and microthrombi after renal ischemia-reperfusion using a well-characterized model. Renal exosomes or the fibrinolytic urokinase, administered after renal failure was established, improved microvascular flow, coagulation, renal function, and histology. Data demonstrate that intrarenal clotting results in sustained ischemia amenable to therapy that improves both function and postischemic inflammation.

ISCHEMIC REPERFUSION INJURY IN HYPERTENSIVE RAT HEART

Objective: In patients with cardiovascular disease, myocardial ischaemia reperfusion damage is the leading cause of death. Sustained myocardial ischaemia–reperfusion causes cardiomyocyte death and coronary microvascular injury in different ways. Patients with hypertension who undergo cardiac ischemia-reperfusion have more severe clinical outcomes. Design and method: The mechanism, on the other hand, is missing. We use an angiotensin II successfully produced hypertension rat model to investigate the effect of hypertension on cardiac ischemia-reperfusion injury. We successfully established in vitro myocardial ischemia-reperfusion in normal and hypertensive rat hearts using the Langendorff perfusion system. Results: Our results reveal that after 30 minutes of ischemia and an hour of reperfusion, the beating pattern of the hypertensive heart was poorer than that of the sham heart. We also used a Transmission Electron Microscope to examine the morphology of myocardial cells and mitochondria, and discovered that the mitondria structure was dramatically destroyed in the hypertension model compared to the sham model, and that some myocytes in the hypertension model have abnormal morphology after 30 minutes of ischemia and an hour of reperfusion. To assess mitochondrial function, mitochondria were extracted from an ischemia-reperfused heart and Mitochondrial Function Indexes were calculated. When oligomycin was used to block ATP synthase, the formation of reactive oxygen species (ROS) and mitochondrial membrane potential MMP increased considerably in the hypertension group. Furthermore, when FCCP was utilized as a proton collapser and antimycin A was used to block mitochondrial complex III, the generation of reactive oxygen species (ROS) mitochondrial membrane potential MMP in the hypertension group rose significantly at add additional oil substrate. When the hypertension group is given the substrate succinate or oligomycin to block ATP synthase, oxygen consumption increases significantly. Conclusions: Taken together, our research reveals that hypertension can significantly increase the damage caused by myocardial ischemia reperfusion. As a result, hypertension during myocardial ischemia should be given special attention.

Vascular myogenic control of tibial bone blood flow in young healthy individuals

Bone health is critically dependent on adequate blood flow supplied by its extensive vascular network. Without adequate perfusion to provide oxygen and essential nutrients critical for bone metabolism, nearly all skeletal functions are compromised. However, despite the importance of blood flow to bone, regulation of bone blood flow is poorly understood in humans. The broad hypothesis of the current work is that the primary regulators of blood flow to bone are not different from other vascular beds. We have recently shown that sympathetic innervation of the bone vasculature has an active role in controlling bone blood flow in young healthy individuals. This work furthers our previous findings by investigating additional key bone blood flow regulators ‐ myogenic vasodilation and vasoconstriction. While vascular myogenic control has been investigated in soft tissue, to our knowledge there has been no research in the bone vasculature in humans, with only a handful of animal studies.In young healthy individuals (N=8), we characterized myogenic control of tibial blood flow via novel custom‐made near infrared spectroscopy (NIRS). Tibial blood flow via NIRS was measured as oxy‐, deoxy‐, and total hemoglobin (Hb). We employed reactive hyperemia and leg dependency to assess myogenic vasodilation and vasoconstriction in the whole calf and in the tibia. The magnitude of maximum myogenic vasodilation was defined by the peak reactive blood flow response to sustained ischemia. Arterial flow to the lower leg was occluded by rapidly inflating a pneumatic thigh cuff above the knee to 220 mmHg in supine subjects. Tibial blood flow was assessed via NIRS and whole leg blood flow velocity in the popliteal artery of the same leg was measured via Doppler ultrasound during 1 min of rest, 10 min of cuff inflation, and 5 min of recovery. Myogenic vasoconstriction was assessed via leg dependency, i.e., during two levels of increased transmural pressure achieved by lowering the leg below heart level. Only tibial blood flow was assessed during 5 min in supine position, 5 min in seated upright position, and 5 min in seated position with legs lowered at 90deg knee flexion.During cuff occlusion, there was a time dependent decrease in bone oxyHb accompanied by an increase in deoxyHb indicating lack of flow with continued metabolism. Tibial total Hb (sum of oxy‐ and deoxy‐Hb) did not change significantly during cuff inflation, but increased rapidly and markedly with cuff release, far surpassing baseline values when flow was restored. A similar overshoot response was seen in whole leg blood flow with cuff release. Thus, the response of tibial flow to reactive hyperemia follows the same behavior as the whole limb, indicating an active myogenic vasodilator response in bone similar to other vascular beds. During leg dependency, despite increases in arterial perfusion pressure at both levels (ΔP, 25.8 + 3.67, and 40.0 + 3.02 mmHg), there was no change in tibial flow (total Hb, ‐0.39 + 7.40, and ‐0.29 + 16.2 μM). Hence, unchanged tibial flow despite increased pressure indicates a compensatory vasoconstrictor response in the tibia. Our results indicate that similar to other vascular beds, myogenic control plays an active role in regulating the bone vasculature in young healthy individuals. Characterizing blood flow regulation in bone constitutes the basis of defining its role in overall bone health and its contribution to numerous bone loss conditions.

Unusual association of Gitelman syndrome with early diagnosis and glomerular proteinuria; a case report

Gitelman syndrome is an autosomal recessive hereditary tubulopathy whose main alteration is at the sodium-chloride symporter in the distal convoluted tubule, characterized by metabolic alkalosis, normotension, hypokalemia, hypomagnesemia and hypocalciuria. Proteinuria and glomerular hyperfiltration (especially at the beginning of clinical course) are not characteristic manifestations of this disease. We present the case of a 25-year-old female with recent diagnosis of Gitelman syndrome who presented with hyperfiltration and glomerular proteinuria, leading to a renal biopsy, which showed hypertrophy of juxtaglomerular apparatus and mesangial proliferation. In electron microscopy focal podocyte detachment was evidenced, which was compatible with secondary focal segmental glomerulosclerosis (FSGS). This case of association of tubulopathy with secondary glomerulopathy of early presentation, shows the final pathway in this disease, when generating sustained renal ischemia due to the increased activity of renin-angiotensin-aldosterone system (RAAS). Renal biopsy and electron microscopy proved to be useful to define prognosis, early recognition of progression and adjust treatment in this patient.

CTLA4-Ig mediated immunosuppression favors immunotolerance and restores graft in mouse airway transplants

CTLA4-Ig is a potent costimulatory blocker that inhibits T cell activation during alloimmune inflammation and increases graft survival and function. CTLA4-Ig-mediated immunosuppression has been demonstrated to support transplant function in various clinical trials and preclinical settings, but its effects on the balance between regulatory T cells (Tregs) and effector T cells (Teffs), as well as complement activation, are less well investigated. In the present study, we proposed to investigate the effects of CTLA4-Ig mediated immunosuppression on the phase of immunotolerance and the subsequent graft microvascular and epithelial repair during the progression of subepithelial fibrosis in a mouse model of orthotopic trachea transplantation. Briefly, CTLA4-Ig treated allografts (2 mg/kg, I.P.), untreated allografts, and syngrafts were serially monitored for peripheral FOXP3+ Tregs, antibody-mediated complement activation (C3d and C4d), tissue oxygenation, donor-recipient microvascular blood flow, and subsequent tissue remodeling following transplantation. Our data demonstrate that CTLA4-Ig mediated immunosuppression significantly results in late increases in both peripheral CD4+/CD8+ FOXP3+ Tregs and serum IL-10, but prevents the microvascular deposition of IgG, complement factor C3d, and epithelial C4d respectively, which proportionally improved blood flow and tissue oxygenation in the graft and, thus, promotes graft repair. Also, it restored the airway lumen, epithelium, and prevented the progression of subepithelial collagen deposition up to 90 days after transplantation. This study demonstrates that CTLA4-Ig-mediated immunosuppression potentially modulates both effector response and a late surge of regulatory activity to preserve graft microvasculature and rescue allograft from sustained hypoxia and ischemia and thereby limits subepithelial fibrosis.

Involvement of Estrogen Receptor and Mitochondrial KATP Channels in Cardioprotective Effect of Remote Aortic Preconditioning in Isolated Rat Heart

The present study was designed to investigate the role of estrogen receptor and KATP channel in cardioprotective effect of remote aortic preconditioning in rat heart. Remote preconditioning is a phenomenon in which brief episodes of ischemia and reperfusion to remote organs protect the target organ against sustained ischemia/ reperfusion induced injury. Protective effects of remote aortic preconditioning are well established in the heart, but their mechanisms still remain to be elucidated. Remote aortic preconditioning in rats was produced by introducing four episodes of ischemia and reperfusion, each comprising of 5 min occlusion and 5 min reperfusion, through abdominal aorta. Perfused rat heart was isolated and subjected to global ischemia for 30 min followed by reperfusion for 120 min. The degree of cardiac injury was assessed by analysing the level of lactate dehydrogenase, creatin kinase, reactive oxygen species and nitrite in coronary effluent. Myocardial infarct size was also estimated macroscopically using tetrazolium tri chloride staining. Ethylinestradiol (10 μg/kg, orally) as estrogen receptor agonist was noted to reproduce remote aortic preconditioning mediated cardioprotection in ovariectomized rat. However, administration of glibenclamide along with or prior to ethylinestradiol abolished cardioprotection. Moreover, glibenclamide a KATP channel blocker, abolish cardioprotective effect of remote aortic preconditioning with daidzein a caveolin inhibitor (0.2 mg/kg subcutaneous). Ethylinestradiol significantly increased the release of nitric oxide and restored the attenuated cardioprotective effect of remote aortic preconditioning. These data provide the evidence that estrogen receptor activation involved in cardioprotective effect of remote aortic preconditioning-mediated trough opening of KATP channels.

Medicinal Plants with Cardioprotective Potency and Some Possible Cardiac Biomarkers for Monitoring and Diagnosing Myocardial Infarction: A Review

Following the increasing rate of Cardiovascular diseases, actions have been taken and geared towards the discovery of new leads (drugs) since the existing drugs treat and manage some of these Cardiovascular ailments but with proven adverse effects on the side of the patients. Coronary artery disease which is also called Ischemic heart disease is a crucial problem worldwide, and it's known as a major non-transmissible disease. A good example of ischemic heart disease is acute myocardial infarction (MI), and its manifest due to inequality between coronary blood supply and myocardial demand. Sustained ischemia causes myocardial infarction, which leads to myocardial cell death. Cardiac biomarkers are enzymes/proteins that are used as essential tools in cardiology for primary and secondary prevention, diagnosis and management of acute myocardial infarction and other heart-related issues. The treatment and management of diseases in the African continent are achieved mostly with traditional medicine, and Plants are known to contain active components which possess medical properties that are harnessed for the treatment of different diseases. So many medicinal plants have shown to be potent in the treatment and management of this life-threatening condition known as acute myocardial infarction (heart attack). Some research-proven cardioprotective plants and possible tools for evaluating their potency are reviews in this article.

Glycosylated apolipoprotein J in cardiac ischaemia: molecular processing and circulating levels in patients with acute ischaemic events.

Using proteomics, we previously found that serum levels of glycosylated (Glyc) forms of apolipoprotein J (ApoJ), a cytoprotective and anti-oxidant protein, decrease in the early phase of acute myocardial infarction (AMI). We aimed to investigate: (i) ApoJ-Glyc intracellular distribution and secretion during ischaemia; (ii) the early changes in circulating ApoJ-Glyc during AMI; and (iii) associations between ApoJ-Glyc and residual ischaemic risk post-AMI. Glycosylated apolipoprotein J was investigated in: (i) cells from different organ/tissue origin; (ii) a pig model of AMI; (iii) de novo AMI patients (n = 38) at admission within the first 6 h of chest pain onset and without troponin T elevation at presentation (early AMI); (iv) ST-elevation myocardial infarction patients (n = 212) who were followed up for 6 months; and (v) a control group without any overt cardiovascular disease (n = 144). Inducing simulated ischaemia in isolated cardiac cells resulted in an increased intracellular accumulation of non-glycosylated ApoJ forms. A significant decrease in ApoJ-Glyc circulating levels was seen 15 min after ischaemia onset in pigs. Glycosylated apolipoprotein J levels showed a 45% decrease in early AMI patients compared with non-ischaemic patients (P < 0.0001), discriminating the presence of the ischaemic event (area under the curve: 0.934; P < 0.0001). ST-elevation myocardial infarction patients with lower ApoJ-Glyc levels at admission showed a higher rate of recurrent ischaemic events and mortality after 6-month follow-up (P = 0.008). These results indicate that ischaemia induces an intracellular accumulation of non-glycosylated ApoJ and a reduction in ApoJ-Glyc secretion. Glycosylated apolipoprotein J circulating levels are reduced very early after ischaemia onset. Its continuous decrease indicates a worsening in the evolution of the cardiac event, likely identifying patients with sustained ischaemia after AMI.

Calcium and integrin binding protein 1 (CIB1) induces myocardial fibrosis in myocardial infarction via regulating the PI3K/Akt pathway.

Myocardial infarction (MI) is a severe coronary artery disease resulted from substantial and sustained ischemia. Abnormal upregulation of calcium and integrin binding protein 1 (CIB1) has been found in several cardiovascular diseases. In this study, we established a mouse model of MI by permanent ligation of the left anterior descending coronary artery. CIB1 was upregulated in the heart of MI mice. Notably, CIB1 knockdown by intramuscular injection of lentivirus-mediated short hairpin RNA (shRNA) targeting Cib1 improved cardiac function and attenuated myocardial hypertrophy and infarct area in MI mice. MI-induced upregulation of α-SMA, vimentin, Collagen I, and Collagen III, which resulted in collagen production and myocardial fibrosis, were regressed by CIB1 silencing. In vitro, cardiac fibroblasts (CFs) isolated from mice were subjected to angiotensin II (Ang II) treatment. Inhibition of CIB1 downregulated the expression of α-SMA, vimentin, Collagen I, and Collagen III in Ang II-treated CFs. Moreover, CIB1 knockdown inhibited Ang II-induced phosphorylation of PI3K-p85 and Akt in CFs. The effect of CIB1 knockdown on Ang II-induced cellular injury was comparable to that of LY294002, a specific inhibitor of the PI3K/Akt pathway. We demonstrated that MI-induced cardiac hypertrophy, myocardial fibrosis, and cardiac dysfunction might be attributed to the upregulation of CIB1 in MI mice. Downregulation of CIB1 alleviated myocardial fibrosis and cardiac dysfunction by decreasing the expression of α-SMA, vimentin, Collagen I, and Collagen III via inhibiting the PI3K/Akt pathway. Therefore, CIB1 may be a potential target for MI treatment.

Refining murine heterotopic heart transplantation: A model to study ischemia and reperfusion injury in donation after circulatory death hearts.

Heart transplantation is a lifesaving procedure, which is limited by the availability of donor hearts. Using hearts from donors after circulatory death, which have sustained global ischemia, requires thorough studies on reliable and reproducible models that developing researchers may not have mastered. By combining the most recent literature and our recommendations based on observations and trials and errors, the methods here detail a sound in vivo heterotopic heart transplantation model for rats in which protective interventions on the ischemic heart can be studied, and thus allowing the scientific community to advance organ preservation research. Knowledge gathered from reproducible animal models allow for successful translation to clinical studies.

A Swine Hind Limb Ischemia Model Useful for Testing Peripheral Artery Disease Therapeutics.

Currently, there is no large animal model of sustained limb ischemia suitable for testing novel angiogenic therapeutics for peripheral artery disease (PAD) such as drugs, genes, materials, or cells. We created a large animal model suitable for efficacy assessment of these therapies by testing 3 swine hind limb ischemia (HLI) variations and quantifying vascular perfusion, muscle histology, and limb function. Ligation of the ipsilateral external and bilateral internal iliac arteries produced sustained gait dysfunction compared to isolated external iliac or unilateral external and internal iliac artery ligations. Hyperemia-dependent muscle perfusion deficits, depressed limb blood pressure, arteriogenesis, muscle atrophy, and microscopic myopathy were quantifiable in ischemic limbs 6 weeks post-ligation. Porcine mesenchymal stromal cells (MSCs) engineered to express a reporter gene were visualized post-administration via positron emission tomography (PET) in vivo. These results establish a preclinical platform enabling better optimization of PAD therapies, including cellular therapeutics, increasing bench-to-bedside translational success. A preclinical platform for porcine studies of peripheral artery disease therapies including (1) a hind limb ischemia model and (2) non-invasive MSC viability and retention assessment via PET.