Ulinastatin attenuated cardiac ischaemia/reperfusion injury by suppressing activation of the tissue kallikrein-kinin system.

BACKGROUND AND PURPOSE: Ulinastatin has beneficial effects in patients undergoing coronary artery bypass grafting (CABG) surgery due to its anti-inflammatory properties, but the underlying mechanism remains unclear. EXPERIMENTAL APPROACH: We used samples from patients undergoing CABG, a model of cardiac ischaemia-reperfusion injury (IRI) in mice and murine cardiac endothelial cell cultures to investigate links between ulinastatin, the kallikrein-kinin system (KKS), endothelial dysfunction and cardiac inflammation in the response to ischaemia/reperfusion injury (IRI). These links were assessed using clinical investigations, in vitro and in vivo experiments and RNA sequencing analysis. KEY RESULTS: Ulinastatin inhibited the activity of tissue kallikrein, a key enzyme of the KKS, at 24 h after CABG surgery, which was verified in our murine cardiac ischaemia-reperfusion model. Under normal conditions, ulinastatin only inhibited kallikrein activity but did not affect bradykinin (B1/B2) receptors. Ulinastatin protected against IRI, in vivo and in vitro, by suppressing activation of the kallikrein-kinin system and down-regulating B1/B2 receptor-related signalling pathways including ERK/ iNOS, which resulted in enhanced endothelial barrier function, mitigation of inflammation and oedema, decreased infarct size, improved cardiac function and decreased mortality. Inhibition of kallikrein and knockdown of B1, but not B2 receptors prevented ERK translocation into the nucleus, reducing reperfusion-induced injury in murine cardiac endothelial cells. CONCLUSIONS AND IMPLICATIONS: Treatment with ulinastatin exerts a protective influence on cardiac reperfusion by suppressing activation of the kallikrein-kinin system. Our findings highlight the potential of targeting kallikrein /bradykinin receptors to alleviate endothelial dysfunction, thus improving cardiac IRI.

Right coronary ischaemia caused by a sinus of Valsalva aneurysm improved by releasing mechanical stretch: a case report.

Background: A sinus of Valsalva aneurysm involving a single cusp is a rare condition, and coronary computed tomography angiography with fractional flow reserve-computed tomography helps evaluate not only the anatomical aspects of the aneurysm and coronary artery but also the physiological details of coronary artery disease. Case summary: A 71-year-old woman presented with exertional chest pain and dyspnoea. Enhanced computed tomography revealed an aneurysmal change in the right sinus of Valsalva, and coronary computed tomography angiography revealed diffuse narrowing of the proximal segment of right coronary artery due to mechanical stretching by the large Valsalva aneurysm. Fractional flow reserve-computed tomography revealed a significantly low fractional flow reserve (0.50 in the distal right coronary artery). A modified Bentall procedure was performed with a 21 mm bioprosthetic valve and a 24 mm Valsalva graft conduit for the aortic root aneurysm; mitral valve annuloplasty was performed for mitral valve regurgitation. Post-operative coronary computed tomography angiography revealed no significant stenosis in the proximal segment of the right coronary artery. Furthermore, fractional flow reserve-computed tomography revealed a normalized fractional flow reserve in the distal right coronary artery. The patient experienced relief from chest pain and was discharged 19 days after the surgery. Discussion: A right coronary sinus of Valsalva aneurysm, which caused right coronary artery ischaemia, was successfully treated using a modified Bentall procedure. Coronary computed tomography angiography and fractional flow reserve-computed tomography revealed anatomical and functional improvements in the right coronary artery ischaemia post-operatively.

Acute Lower Limb Ischaemia as a Presenting Sign of Atrial Myxoma: Case Report and Scoping Review of the Literature.

Objective: Cardiac myxomas (CMs) are the most common primary cardiac tumour in adults. They are a rare cause of peripheral embolisation and may present as acute lower limb ischaemia (ALI). A scoping review was undertaken and a case of ALI due to CM embolisation is presented in this paper. Methods: MEDLINE, Scopus, and Embase were systematically searched for studies reporting data on ALI as a presentation of CM embolisation. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) was followed. Results: A healthy 26 year old female presented to the emergency department with bilateral ALI. Urgent bilateral aorto-iliac embolectomy and distal embolectomy of the left femoropopliteal axis were performed. The retrieved embolic material exhibited a yellowish appearance and jelly like consistency, and histological analysis provided a diagnosis of a myxomatous embolus. Transoesophageal echocardiography confirmed the left atrial origin of a myxomatous tumour, but the residual mass was considered too small for further excision. At a two year clinical follow up, the patient was alive and well without recurrence. Between 1989 and 2023, 59 patients with ALI due to CM embolisation were identified in the literature. An in hospital mortality rate of 12.1% (n = 7) was reported, while the in hospital complication and re-intervention rates were 34.5% (n = 20) and 27.6% (n = 16), respectively. No post-discharge deaths, complications, or re-interventions were reported; fasciotomies were the most reported (n = 10). Post-discharge follow up was reported in 22 (37.3%) patients. Mean follow up was 18.0 ± 18.8 months (range 1-120), and 86.4% of patients (n = 19) were alive and well at last follow up. Conclusion: This review and the associated case report underline that CM embolisation should be considered in healthy young patients presenting with cryptogenic ALI. Early transoesophageal echocardiography and histological analysis of the retrieved embolus are recommended to minimise misdiagnosis in these populations.

Protective effect of salvianolic acid B against myocardial ischemia/reperfusion injury: preclinical systematic evaluation and meta-analysis.

Background: Salvianolic acid B is the most abundant water-soluble component in the traditional Chinese medicine Danshen and can reduce myocardial ischemia-reperfusion (MI/R) injury through multiple targets and pathways. However, the role of SalB in protecting the myocardium from ischemia/reperfusion injury remains unclear. Purpose: To perform a preclinical systematic review and meta-analysis to assess the efficacy of Sal B in an animal model of myocardial infarction/reperfusion (MI/R) and to summarize the potential mechanisms of Sal B against MI/R. Methods: Studies published from inception to March 2024 were systematically searched in PubMed, Web of Science, Embase, China National Knowledge Infrastructure Wanfang, and VIP databases. The methodological quality was determined using the SYRCLE RoB tool. The R software was used to analyze the data. The potential mechanisms are categorized and summarized. Results: 32 studies containing 732 animals were included. The results of the meta-analysis showed that Sal B reduced myocardial infarct size (p < 0.01), and the cardiological indices of CK-MB (p < 0.01), CK (p < 0.01), LDH (p < 0.01), and cTnI (p < 0.01) compared to the control group. In addition, Sal B increased cardiac function indices, such as LVFS (p < 0.01), -dp/dt max (p < 0.01), +dp/dt max (p < 0.01), and cardiac output (p < 0.01). The protective effects of Sal B on the myocardium after I/R may be mediated by attenuating oxidative stress and inflammation, promoting neovascularization, regulating vascular function, and attenuating cardiac myocyte apoptosis. Publication bias was observed in all the included studies. Further studies are required to elucidate the extent of the cardioprotective effects of SalB and the safety of its use. Conclusion: To the best of our knowledge, this is the first meta-analysis of Sal B in the treatment of MI/R injury, and Sal B demonstrated a positive effect on MI/R injury through the modulation of key pathological indicators and multiple signaling pathways. Further studies are needed to elucidate the extent to which SalB exerts its cardioprotective effects and the safety of its use. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/.

Comparison of Clinical Outcomes in Patients with Acute Lower Limb Ischaemia Undergoing Endovascular Therapy and Open Surgical Revascularisation: A Large Scale Analysis in Japan.

OBJECTIVE: The recommended revascularisation methods for acute limb ischaemia (ALI), which is caused by embolism and atherosclerotic thrombosis, include endovascular therapy (EVT) and open surgical revascularisation (OSR); however, treatment choices based on patient characteristics remain controversial. This retrospective analysis from the Japanese Registry of All Cardiac and Vascular Diseases - Diagnosis Procedure Combination database (April 2012 to March 2020) evaluated differences in clinical outcomes and identified prognostic predictors in patients with ALI. METHODS: This study analysed 10 977 patients with lower limb ALI. EVT was defined as catheter directed thrombolysis, percutaneous thrombectomy, or percutaneous angioplasty with balloon dilatation and or stenting. OSR was defined as Fogarty thrombectomy, bypass surgery, or thromboendarterectomy. The EVT and OSR groups were compared after propensity score matching (PSM) considering ten clinical covariables. RESULTS: The EVT group had more patients at higher risk of atherosclerotic disease than the OSR group. The OSR group had more patients at a higher risk of embolism, including atrial fibrillation and atrial flutter, than the EVT group. In the EVT group, 20.4% of patients underwent catheter directed thrombolysis using urokinase, the only thrombolytic agent available in Japan that is covered under insurance. After PSM, in hospital mortality (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.11 - 1.59; p = .002), major amputation rate (OR 1.43, 95% CI 1.19 - 1.72; p < .001), major amputation and or death rate (OR 1.42, 95% CI 1.24 - 1.62; p < .001), and total hospitalisation cost (1.16 vs. 0.97 million yen; p < .001) were statistically significantly more common in the EVT group. In interaction analyses, peripheral artery disease (PAD) was a factor responsible for reducing OSR efficacy in terms of major amputation and or death rate (with PAD, OR 0.94, 95% CI 0.68 - 1.29; without PAD, OR 1.56, 95% CI 1.34 - 1.82; p = .004). CONCLUSION: In Japan, EVT was a less effective primary treatment for patients with ALI than OSR, except for those with PAD.

Changes in early endosomes in rat hippocampal CA1 neurons after transient global cerebral ischaemia.

INTRODUCTION: Transient global ischaemia in rodents causes selective loss of hippocampal CA1 neurons, but the potential involvement of endocytic pathways has not been fully explored. The aim of this study was to investigate the changes in early endosomes in the CA1 subfield after ischaemia and reperfusion. MATERIALS AND METHODS: A four-vessel occlusion (4-VO) model was established in Wistar rats to induce 13 minutes of global cerebral ischaemia. Neuronal death was detected by Fluoro-Jade B (FJ-B) staining at various intervals after reperfusion, and intracellular membrane changes in ischaemic neurons were revealed using DiOC6(3), a lipophilic fluorescent probe. Ras-related protein Rab5 (Rab5) immunostaining was performed to detect changes in early endosomes in ischaemic neurons. Western blot analysis was used to confirm the morphological observations on Rab5 in the CA1 hippocampal subfield. RESULTS: FJ-B staining confirmed progressive neuronal death in the CA1 subfield in ischaemic rats after reperfusion. DiOC6(3) staining revealed abnormally increased membranous components in ischaemic CA1 neurons. Specifically, early endosomes, as labelled by Rab5 immunostaining, significantly increased in number and size in CA1 neurons at 1.5 and 2 days post-reperfusion, followed by rupture at day 3 and a decrease in staining intensity at day 7 post-reperfusion. Western blot analysis confirmed a significant upregulation of Rab5 protein levels at day 2, which returned to near control levels by day 7. CONCLUSIONS: Our study revealed significant changes in the dynamics of early endosomes in CA1 neurons after ischaemia-reperfusion injury. The initial increase in the area fraction of early endosomes in CA1 neurons may reflect an upregulation of endocytic activity, whereas the fragmentation and reduction of early endosomes at the later stage may indicate a failure of adaptive mechanisms of ischaemic neurons against ischaemia-induced death. Understanding the temporal dynamics of early endosomes provides critical insights into the cellular mechanisms that govern fate of CA1 hippocampal neuronsl after ischaemia/reperfusion.

Early life stress exacerbates the obesogenic and anxiogenic effects of a Western diet without worsening cardiac ischaemic tolerance in male mice.

Early life stress (ELS) and a Western diet (WD) promote mood and cardiovascular disorders, however, how these risks interact in disease pathogenesis is unclear. We assessed effects of ELS with or without a subsequent WD on behaviour, cardiometabolic risk factors, and cardiac function/ischaemic tolerance in male mice. Fifty-six new-born male C57BL/6J mice were randomly allocated to a control group (CON) undisturbed before weaning, or to maternal separation (3h/day) and early (postnatal day 17) weaning (MSEW). Mice consumed standard rodent chow (CON, n = 14; MSEW, n = 15) or WD chow (WD, n = 19; MSEW + WD, n = 19) from week 8 to 24. Fasted blood was sampled and open field test and elevated plus maze (EPM) tests undertaken at 7, 15, and 23 weeks of age, with hearts excised at 24 weeks for Langendorff perfusion (evaluating pre- and post-ischaemic function). MSEW alone transiently increased open field activity at 7 weeks; body weight and serum triglycerides at 4 and 7 weeks, respectively; and final blood glucose levels and insulin resistance at 23 weeks. WD increased insulin resistance and body weight gain, the latter potentiated by MSEW. MSEW + WD was anxiogenic, reducing EPM open arm activity vs. WD alone. Although MSEW had modest metabolic effects and did not influence cardiac function or ischaemic tolerance in lean mice, it exacerbated weight gain and anxiogenesis, and improved ischaemic tolerance in WD fed animals. MSEW-induced increases in body weight (obesity) in WD fed animals in the absence of changes in insulin resistance may have protected the hearts of these mice.

Hydrogen attenuates ischaemia-reperfusion injury in skeletal muscles post-limb replantation by activating the NRF2/HO-1 signalling pathway to reduce BAX expression.

Background: Ischaemia-reperfusion injury (IRI) is a critical complication post-limb replantation. The oxidative stress and cellular apoptosis due to IRI considerably hinder the healing process. This study aimed to investigate the modulatory effects of pre-perfusion with hydrogen-rich heparin sodium on the nuclear factor erythroid 2-related factor 2 (NRF2)/haeme oxygenase-1 (HO-1) pathway and its potential mechanisms in mitigating skeletal muscle IRI post-limb replantation. Methods: Forty healthy Sprague-Dawley rats (250-300 g) were classified into five groups (n = 8 each): normal control, IRI + heparin sodium pre-perfusion (heparin group), IRI + hydrogen-rich heparin sodium pre-perfusion (hydrogen-rich heparin group), IRI + hydrogen-rich heparin sodium pre-perfusion + NRF2 inhibitor (hydrogen-rich heparin + all-trans retinoic acid [ATRA] group), and IRI + heparin sodium pre-perfusion + NRF2 inhibitor (heparin + ATRA group). The activation of the NRF2/HO-1 pathway in skeletal muscle IRI was evaluated based on HO-1 expression using western blotting and immunofluorescence. Furthermore, haematoxylin and eosin staining and transmission electron microscopy were employed to determine the histopathological characteristics. Additionally, superoxide dismutase and malondialdehyde levels in skeletal muscle tissue were measured to assess antioxidant capacity and the degree of oxidative stress damage. Tissue hypoxia was assessed based on hypoxia-inducible factor 1-alpha expression, whereas apoptosis markers BCL-2-associated X protein (BAX) and Caspase-3 in skeletal muscle tissues were analysed using western blotting with terminal deoxynucleotidyl transferase dUTP nick end labelling staining to quantify cell apoptosis. Results: Compared with the control group, the heparin group exhibited significant pathological changes, including inflammatory infiltration and cellular hypertrophy, with increased apoptosis and oxidative stress. Notably, NRF2 suppression aggravated these effects. However, hydrogen-rich heparin sodium prominently activated the NRF2/HO-1 pathway, enhancing antioxidant defence and reducing BAX/Caspase-3-mediated apoptosis, thereby mitigating IRI-induced damage. The use of an NRF2 inhibitor to inhibit NRF2 excitation by hydrogen-rich heparin sodium notably weakened NRF2 activation and the antioxidant response, resulting in a substantial increase in cellular apoptosis. Conclusion: Pre-perfusion with hydrogen-rich heparin sodium markedly diminishes the BAX/Caspase-3-mediated apoptotic pathway in skeletal muscle tissues with IRI through the excitation of the NRF2/HO-1 pathway.

SEA Alleviates Hepatic Ischaemia-Reperfusion Injury by Promoting M2 Macrophage Polarisation.

Hepatic ischaemia-reperfusion (I/R) injury is a frequent and nearly inevitable pathophysiological process without widely accepted effective therapy. Soluble egg antigen (SEA) of Schistosoma japonicum (S. japonicum) is the main mediators capable of regulating immunological activities and has received increased attention in immune-mediated diseases. But its role in hepatic I/R injury has not been well defined. This study aimed to elucidate whether SEA protects liver against hepatic I/R injury and explore underlying mechanism. After intraperitoneal injecting SEA three times a week for 4 weeks, mice underwent 70% hepatic I/R injury. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), haematoxylin-eosin (HE) and TdT-mediated dUTP nick-end labelling (TUNEL) staining were used to evaluate liver injury. The severity related to the inflammatory response was also investigated. Furthermore, immunofluorescence was used to detect macrophage polarisation. Compared with the hepatic I/R injury group, SEA pretreatment significantly alleviated hepatic I/R injury induced liver damage, apoptosis and inflammatory. Interestingly, SEA enhanced the polarisation of macrophages towards M2 macrophages in vivo. We are the first to investigate the therapeutic efficacy of S. japonicum SEA in a hepatic I/R injury model in mice. We provided the first direct evidence that SEA attenuated hepatic I/R injury by promoting M2 macrophage polarisation.

Bilateral Transankle Intervention as a Critical Determinant of Successful Revascularisation in Complex Peripheral Arterial Disease.

Introduction: Establishing optimal vascular access sites is important for the procedural success of endovascular treatment (EVT) and the patient's comfort afterwards. Among the variety of vascular access sites, the transankle intervention (TAI) has been used more recently; however, there have been no reports of complex lower extremity arterial disease lesions treated with the TAI manoeuvre. Report: An 82 year old man with chronic limb threatening ischaemia in both lower extremities underwent EVT for bilateral long segment occlusion from the iliac arteries to the superficial femoral artery (SFA). The right posterior tibial artery was punctured under extravascular ultrasound guidance and a Parent Select 5082 guide sheath was inserted. The guidewire was manipulated under intravascular ultrasound (IVUS) guidance. When the first guidewire entered the subintimal space, the second guidewire was manipulated to advance through the intraplaque route, while monitoring it using IVUS. The intraluminal space of the right common iliac artery was reached by repeating these procedures. A self expandable stent was deployed in the external iliac artery and drug coated balloons were inflated from the common femoral artery to the SFA; good vascular patency and favourable blood flow were confirmed. Subsequently, a similar TAI procedure was performed from the left dorsalis pedis artery, and successful revascularisation was achieved from the left common iliac artery to the SFA. After revascularisation, the persistent pain disappeared in the right lower limb and the wound healed favourably in the left lower limb. Conclusion: In this case of complex chronic limb threatening ischaemia, the TAI strategy worked favourably for successful revascularisation. Transankle intervention can provide various advantages for successful EVT.

Impact of Tourniquet Use in Major Lower Limb Amputation: A Systematic Review and Meta-analysis.

OBJECTIVE: Intra-operative blood loss is a significant complication of major lower limb amputation (MLLA). This systematic review and meta-analysis assessed the effect of tourniquet use on patients undergoing amputation. DATA SOURCES: Embase, MEDLINE, and Cochrane databases were searched from inception to April 2024. REVIEW METHODS: Inclusion criteria were any study design assessing MLLA with and without tourniquet use. Primary outcomes were peri-operative blood loss and transfusion requirements. Secondary outcomes were operative duration, surgical site infection, stump revision, and death. Articles were screened and data extracted independently by two reviewers, then pooled using random effects meta-analysis, and presented with their GRADE certainty. Risk of bias was assessed using ROBINS-I and Cochrane RoB 2 tools. RESULTS: Seven studies (one randomised controlled trial [RCT] and six cohort studies) were included, totalling 1 018 limbs (412 tourniquet, 606 non-tourniquet). Intra-operative blood loss was lower with tourniquet use (mean difference [MD] -192.09 mL; 95% confidence interval [CI] -291.67 - -92.52; p < .001); however, there was no statistically significant difference in total blood loss measured over the first three to four post-operative days (MD -254.66 mL; 95% CI -568.12 - 58.80; p = .11). Post-operative haemoglobin decrease was lower for tourniquet patients (MD -0.55 g/dL; 95% CI -0.80 - -0.31; p < .001). The odds ratio (OR) for requiring blood transfusion was 0.65 (95% CI 0.38 - 1.11; p = .11) for tourniquet vs. non-tourniquet patients, with no statistically significant difference in number of units transfused per patient (MD -0.35, 95% CI -0.72 - 0.03; p = .070). Operation length was shorter with tourniquet use (MD -8.69 minutes, 95% CI -15.95 - -1.42; p = .020). There was no statistically significant difference in rates of surgical site infection (OR 1.07, 95% CI 0.60 - 1.90; p = .82), stump revision (OR 0.71, 95% CI 0.43 - 1.16; p = .17), or death (OR 0.80, 95% CI 0.49 - 1.30; p = .36). GRADE certainty was low or very low for all outcomes. CONCLUSION: Tourniquet use may be associated with reduced post-operative haemoglobin decrease and operative duration, without negative consequences on stump infection, revision, and mortality. However, most data are observational. Further RCTs are needed to generate higher quality evidence.

Designing a platform/adaptive randomised controlled trial for peripheral arterial disease (PAD) - The PAEDIS international platform trial development project.

Background: Peripheral artery disease (PAD) is a common health problem. There are several technologies, medications, and interventions that aim to improve or treat PAD in people with symptomatic disease. Most of these technologies, however, have been untested in high-quality randomised studies assessing effectiveness and their interactions remain unknown. We developed a proposed design for an international randomised controlled trial assessing multiple PAD treatments. Methods: Over the course of 11 months (2023) several workshops and reviews of the literature took place. More specific, the proposed platform trial was designed with 44 people with PAD and 112 experts from across the world, in five work packages. The most relevant PAD treatment with unproven effectiveness were identified and key trial components as well as success criteria were defined. With input from five clinical trials units, the final format of a potential platform PAD trial in primary and secondary care was then proposed for funding. Results: The proposed platform PAD randomised trial involved two major multi-arm multi-stage randomised studies, assessing PAD treatments in the community setting (1 st package) and then secondary care (2 nd package). The 1 st package involved people with claudication and the 2 nd package involves people with chronic limb threatening ischaemia (CLTI). Conclusions: A platform PAD trial involves many challenges in terms of both design and delivery. The proposed design involving both people with claudication and CLTI will hopefully act as a blueprint for future work in this area.

Background: One in five people over 55 years of age have blockages in the arteries carrying blood to their legs. This is called peripheral artery disease or PAD. It can cause severe leg pain or skin and muscles of the legs dying due to limited blood supply. Doctors have been treating PAD using surgery for years. Keyhole artery surgery has recently been developed. Also, new medications are available for people with blocked arteries. Several new devices and medications are invented every year for PAD. Unfortunately, we don't know whether these new medications and devices actually work. This is causing uncertainty when making treatment decisions, leads to unnecessary leg amputations, and deaths. Also, these new treatments might be costing society far more money than the older treatments. In this work, we designed the best possible research to assess all these new PAD treatments in the next few years. Design & methods: This project took place in 2023 in five different stages (called work packages), involving 44 patients, carers, and 112 experts from many countries and the NHS. We looked up all treatments and medications available for this condition. We then agreed on what would make our future research successful. After that, we set up groups of patients and experts to design the research. We agreed on the final design of this research. Results: The proposed study should involve people with claudication in the 1 st stage and people with leg gangrene in the 2 nd stage. We agreed to test treatment like exercise and open surgery vs. keyhole surgery. The best way to assess treatments is to look at which one leads to less deaths and leg amputations. The results of this work described in this article will act as a blueprint for future research in this area.

An adenosinergic positive feedback loop extends pharmacological cardioprotection duration.

BACKGROUND AND PURPOSE: Adenosine receptor activation induces delayed, sustained cardioprotection against ischaemia-reperfusion (IR) injury (24-72 h), but the mechanisms underlying extended cardioprotection duration remain unresolved. We hypothesized that a positive feedback loop involving adenosine receptor-induced proteasomal degradation of adenosine kinase (ADK) and decreased myocardial adenosine metabolism extends the duration of cardioprotection. EXPERIMENTAL APPROACH: Mice were administered an ADK inhibitor, ABT-702, to induce endogenous adenosine signalling. Cardiac ADK protein and mRNA levels were analysed 24-120 h later. Theophylline or bortezomib was administered 24 h after ABT-702 to examine the late roles of adenosine receptors or proteasomal activity, respectively, in ADK expression and cardioprotection at 72 h. Coronary flow and IR tolerance were analysed by Langendorff technique. The potential for continuous adenosinergic cardioprotection was examined using heterozygous, cardiac-specific ADK KO (cADK+/-) mice. Cardiac ADK expression was also examined after A1 or A3 receptor agonist, phenylephrine, lipopolysaccharide or sildenafil administration. KEY RESULTS: ABT-702 treatment decreased ADK protein content and provided cardioprotection from 24 to 72 h. ADK mRNA upregulation restored ADK protein after 96-120 h. Adenosine receptor or proteasome inhibition at 24 h reversed ABT-702-induced ADK protein deficit and cardioprotection at 72 h. cADK+/- hearts exhibited continuous cardioprotection. Diverse preconditioning agents also diminished cardiac ADK protein expression. CONCLUSION AND IMPLICATIONS: A positive feedback loop driven by adenosine receptor-induced ADK degradation and renewed adenosine signalling extends the duration of cardioprotection by ABT-702 and possibly other preconditioning agents. The therapeutic potential of continuous adenosinergic cardioprotection is demonstrated in cADK+/- hearts.

Anticoagulation in embolic acute limb ischaemia-an observational study.

The management of embolic acute limb ischaemia commonly involves determining aetiology and performing emergency invasive procedures. This detailed study aimed to determine the impact of manipulation of anticoagulation in the aetiology of emboli in acute limb ischaemia and determine the efficacy of primary anticoagulation therapy vs. invasive interventions. Material and methods: Data collection was conducted at a single institution on a cohort of patients presenting consecutively with embolic acute limb ischaemia over one year. Two groups were compared, one receiving anticoagulation as primary therapy with those undergoing invasive treatment as the internal comparison group. Results: A likely haematological causation was identified in 22 of 38 presentations, related to interruption of anticoagulation in cardiac conditions, the majority atrial fibrillation (n=12), or hypercoagulable states (n=10). Limb salvage was pursued in 36 patients employing anticoagulation (n=19) or surgical embolectomy (n=17) as the primary therapy in upper and lower limbs (n=17 vs n=19 respectively). Despite delays often well beyond six hours and a range of ischaemic severity in both groups, 35 of 36 patients achieved full or substantive restoration of function with improved perfusion. Regarding anatomical distribution of arterial disease and therapy, three patients with multi-level disease proceeded to embolectomy following anticoagulation. Embolectomy was undertaken most often for proximal emboli and more profound paralysis. Conclusions: Anticoagulation and coagulopathy are commonly implicated in the aetiology of arterial emboli, with omission of effective anticoagulation in atrial fibrillation being associated in almost 1/3 of presentations. Whilst more profound limb paralysis and proximal or multi-level disease tended to be managed surgically, primary anticoagulation therapy alone or with a secondary embolectomy was effective across the spectrum of ischaemia severity and despite significant delays beyond guideline recommendations.

Phillygenin attenuates cell apoptosis and microglia activation in cerebral ischaemia-reperfusion rats through activation of peroxisome proliferator-activated receptor γ.

Ischaemic stroke is a common condition that can lead to cerebral ischaemia-reperfusion injury. Phillygenin (PHI), a natural bioactive compound derived from Forsythia suspensa, has been shown to play a crucial role in regulating inflammation across various diseases. However, its specific regulatory effects in ischaemic stroke progression remain unclear. In this study, we established a middle cerebral artery occlusion (MCAO) rat model. Treatment with PHI (50 or 100 mg/kg) significantly reduced cerebral infarction in MCAO rats. PHI treatment also mitigated the increased inflammatory response observed in these rats. Additionally, PHI suppressed microglial activation by reducing iNOS expression, a marker of M1-type polarization of microglia, and attenuated increased brain tissue apoptosis in MCAO rats. Furthermore, PHI's anti-inflammatory effects in MCAO rats were abrogated upon co-administration with GW9662, a peroxisome proliferator-activated receptor γ (PPARγ) inhibitor. In summary, PHI attenuated microglial activation and apoptosis in cerebral ischaemia-reperfusion injury through PPARγ activation, suggesting its potential as a therapeutic agent for mitigating cerebral ischaemia-reperfusion injury.

Altered muscle fibre activation in an antagonistic muscle pair due to perturbed afferent feedback caused by blood flow restriction.

PURPOSE: This study aimed to better understand the coping strategy of the neuromuscular system under perturbed afferent feedback. To this end, the neuromechanical effects of transient blood flow restriction (BFR) compared to atmospheric pressure were investigated in an antagonistic muscle pair. METHODS: Perceived discomfort and neuromechanical parameters (torque and high-density electromyography) were recorded during submaximal isometric ankle dorsiflexion before, during and after BFR. The tibialis anterior and gastrocnemius lateralis muscles were studied in 14 healthy young adults. RESULTS: Discomfort increased during BFR and decreased to baseline level afterwards. The exerted torque and the co-activation index remained constant, whereas the EMG signal energy increased significantly during BFR. Coherence analysis of the delta band remained constant, whereas the alpha band shows an increase during BFR. Median frequency and muscle fibre conduction velocity showed a positive trend during the first minutes of BFR before significantly decreasing. Both parameters exceeded baseline values after cuff deflation. CONCLUSION: Perturbed afferent feedback leads to altered neuromechanical parameters. We assume that increased central drive is required to maintain force output, resulting in changed muscle fibre activity. Glycolytic fast-switch fibres are only active for a short time due to oxygen deprivation and hyperacidity, but fatigue effects predominate in the long term.

Changes in Sex Related Mortality after Revascularisation for Chronic Limb Threatening Ischaemia: A National Observational Study 1994 - 2018.

OBJECTIVE: The aim of this study was compare all cause mortality across three time periods with a focus on sex differences after revascularisation for chronic limb threatening ischaemia between 1994 and 2013 in Sweden. METHODS: In this observational registry study, patients registered in the Swedish vascular registry (Swedvasc), revascularised between 1994 and 2013 with open or endovascular infra-inguinal procedures, were divided into three time periods: 1994 - 1999, 2000 - 2006, and 2007 - 2013. Patients were followed for five years. Poisson regression was used to compare 30 day mortality, presented as adjusted relative risk ratio (aRR). Adjusted restricted mean survival time (aRMST) differences at five years were compared with a generalised linear model. The analyses were adjusted for age, comorbidities, and endovascular or open surgery. Comparison with the general Swedish population was also conducted with age adjusted standardised mortality ratios. Results are presented with the 95% confidence intervals (CI). RESULTS: The study showed increasing 30 day mortality, with an aRR of 1.47 (95% CI 1.31 - 1.65) for women and aRR of 1.20 (95% CI 1.06 - 1.35) for men, per time period. In women, the five year RMST decreased from the first to the third period, with an aRMST of -45 (95% CI -59 - -32) days per period. In men, the aRMST increased 32 (95% CI 18 - 47) days per period. When comparing sexes, women showed lower 30 day mortality and higher five year survival than men in the first time period, but a significantly worse development over time periods than for men. Corresponding findings were observed in comparison with the general Swedish population. CONCLUSION: This study showed an increased 30 day mortality in women and men across the periods, most evident in women. Men showed an increased five year survival across the periods, whereas opposite findings were recorded for women. The dismal trend over time for women could not be explained by increased age or a higher prevalence of comorbidities.

A case of superior mesenteric artery stenting for small intestinal ischaemia caused by superior mesenteric artery invasion of pancreatic cancer.

Superior mesenteric artery (SMA) invasion by a malignant tumour is a serious condition leading to intestinal ischaemia. Although SMA stenting has been reported to be useful for SMA dissection and stenosis caused by atherosclerotic plaque, SMA stenting for stenosis caused by malignant tumour invasion is rarely reported and uncertain. A 75-year-old woman presented intestinal ulcer and melena caused by SMA invasion of unresectable pancreatic cancer. The bare metal stent was implanted for the vessel stenosis, and a small intestinal ulcer was markedly improved after stenting. However, one and a half months after stenting the stent was occluded and a thrombectomy was performed. After thrombectomy, residual stenosis caused by tumour invasion was observed in the stent. The patient suddenly died 2 days after thrombectomy before additional covered stenting for residual stenosis. Stent implantation may be a treatment option for intestinal ischaemia caused by vessel invasion of malignant tumours. On the other hand, re-stenosis of the stent due to tumour ingrowth is a problem, and covered stenting is considered for long-term stent patency.