Surgical approaches for pituitary surgery have evolved considerably since the introduction of endoscopic technology that allows utilisation of the natural endonasal corridor to access the sellar and parasellar region. Post-operative cerebrospinal fluid (CSF) leak remains the main indicator of successful skull-base repair following Transsphenoidal Hypophysectomy (TH). Since the introduction of vascularised nasoseptal flap (NSF) as an option for the reconstruction of the skull base, the morbidity and mortality associated with CSF leak has significantly decreased. 1 However, the role of rigid repair is still controversial, and traditionally, the vomer has been used as the autologous graft of choice. Polydioxanone (PDS) sheet has been reported as an alternative to the current methods of rigid repair in skull-base surgeries. 2 The aim of this study was to evaluate our experience using the PDS as a rigid framework to support our NSF repair following TH.
Background Hyperglycaemia is a common finding in diabetic and non-diabetic patients presenting with ACS, and is a powerful predictor of prognosis and mortality. The role of hyperglycaemia in ischemia-reperfusion injury (IRI) is not fully understood, and whether the Sodium Glucose co-Transporter 1 (SGLT1) plays a role in infarct augmentation, before and/or after reperfusion, remains to be elucidated. However, diabetes clinical trials have shown SGLT inhibition improves cardiovascular outcomes, yet the mechanism is not fully understood. Purpose (1) Characterise the expression of SGLT1 in the myocardium, (2) determine the role of high glucose during IRI, (3) whether SGLT1 is involved in a glucotoxicity injury during IRI, and (4) whether inhibiting SGLT1 with an SGLT inhibitor may reduce infarct size. Methods RT-PCR and in-situ hybridization (RNAScope) techniques were used to detect SGLT1 mRNA expression in Sprague-Dawley whole myocardium and isolated primary cardiomyocytes. An Ex-vivo Langendorff ischemia-reperfusion perfusion model was used to study the effect of high glucose (22mmol) on the myocardium at reperfusion compared to normoglycaemia (11mmol). The mixed SGLT1&2 inhibitor, Phlorizin was introduced following ischaemia, at reperfusion and its effect on infarct size measured using triphenyltetrazolium chloride (TTC) staining. Results RT-PCR found SGLT1 mRNA is expressed in whole myocardium and in individual cardiac chambers. SGLT1 expression was not detected in isolated cardiomyocyte but it is detected in the non-cardiomyocyte population. Cardiomyocytes were found to express mRNA SGLT1 if incubated overnight. RNAscope detected SGLT1 mRNA within intact myocardium: not in the cardiomyocyte, but rather in a perivascular distribution. Importantly, hyperglycaemia (22mmol) at reperfusion increased infarct size (51.80±3.52% vs. 40.80±2.89%; p-value: 0.026) compared to normoglycaemia, and the mixed SGLT inhibitor, Phlorizin, significantly attenuated infarct size (from 64.7±4.2%to 36.6±5.8%; p-value<0.01) when given at reperfusion. Conclusion We have shown that SGLT1 is present in the myocardium, but not expressed in cardiomyocytes. The cell type is yet to be determined, but the distribution of SGLT1 is perivascular. Hyperglycaemia appears augment myocardial infarction and inhibition of SGLT1&2 attenuates this increase. We suspect SGLT1 may plays a role in exacerbating the injurious effect of glucotoxicity during ischemia-reperfusion. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation
Introduction: Hyperglycemia is a common finding in ACS patients in both diabetic and non-diabetic, it is considered a powerful predictor of prognosis and mortality. The role of hyperglycemia in ischemia-reperfusion injury is not fully understood, whether the Sodium Glucose Co-Transporter 1(SGLT1) plays a role in increase injury, before and/or after reperfusion, remains to be elucidated. SGLT2 inhibitors clinical trials have shown significant improvements in cardiovascular outcomes in diabetic and non-diabetic, yet the mechanism is not fully understood and whether SGLT1 plays a role in infarct augmentation remains to be elucidated. Hypothesis: High glucose at reperfusion leads to excess myocardial injury and the increased injury is mediated through the activity of SGLT1. Methods: RT-PCR and in-situ hybridization (RNAScope) combined with Immunofluorescence integrated co detection with different cell marker techniques were used to detect SGLT1 mRNA expression in Sprague-Dawley whole myocardium and Zucker diabetic rats. An Ex-vivo Langendorff ischemia-reperfusion perfusion model was used to study the effect of high glucose on myocardium at reperfusion. Canagliflozin a non-selective SGLT inhibitor (1μmoL/L to block the SGLT1 and SGLT2 transporter and 5nmol/L to block only the SGLT2 transposer) and Mizagliflozin a selective SGLT1 inhibitor (100nmol/L) was introduced following ischemia at two different glucose concentration concentrations at reperfusion and its effect on infarct size measured using triphenyltetrazolium chloride (TTC) staining. Results: Our data reveal that SGLT1 is homogenously expressed throughout the myocardium and is particularly evident within the vasculature. We have also demonstrated that high-glucose mediated injury in the isolated, perfused heart model and it is abrogated through the administration of both mixed SGLT2/SGLT1 inhibitor, canagliflozin, at a dose that inhibits both SGLT2 and SGLT1, and through the administration of novel specific SGLT1 inhibitor, Mizagliflozin. Conclusions: We have shown that SGLT1 is present in the myocardium. Hyperglycemia appears to augment myocardial infarction and inhibition of SGLT1 attenuates this increase.
Background: Hyperglycemia is common during acute myocardial infarction, irrespective of diabetic status, and portends excess mortality. The mechanisms of this adverse outcome remain unelucidated. Objectives: To test the hypothesis that elevated glucose, at the time of reperfusion following myocardial ischemia, is directly injurious to the heart through induction of sodium/glucose-linked transporter 1 (SGLT1) activity. Methods: Ex-vivo, Langendorff rodent models of 35minute global ischemia and 2hour reperfusion injury were utilised, with variable glucose and reciprocal mannitol concentrations maintaining equivalent osmolarity across groups during reperfusion. Infarct size was assessed by tri-phenyltetrazolium staining. SGLT1 expression was determined in rodents by rtPCR, RNAscope and immunohistochemistry and in human with single-cell transcriptomic analysis. Ex-vivo, functional involvement of SGLT1 was determined using three, structurally distinct pharmacological inhibitors: phlorizin, canagliflozin and mizagliflozin. Results: In non-diabetic rodent hearts there was a J-shaped dose-response relationship between reperfusion-glucose concentration and infarct size, an association ameliorated in diabetic heart. Single-cell transcriptomic analysis revealed human myocardial SGLT1 expression equivalent to that seen in rodents at both an RNA and protein level. Diabetic rodent heart SGLT1 expression was significantly reduced compared to non-diabetic, and pharmacological SGLT1 inhibition abrogated excess injury associated with high glucose in non-diabetic heart. Conclusion: Elevated glucose during reperfusion exacerbated myocardial infarction in non-diabetic heart, but this exacerbation was attenuated in diabetic rat heart where SGLT1 expression is suppressed. Inhibiting non-diabetic heart SGLT1 abrogates the excess injury associated with elevated glucose, thus highlighting SGLT1 as a potential clinical translational target to improve outcomes in acute myocardial infarction associated with hyperglycemia.
related to survival in the High-STEACS (High-Sensitivity Troponin in the Evaluation of patients with Acute Coronary Syndrome) randomised controlled trial. Methods The High-STEACS trial was a stepped wedge cluster randomised controlled trial in ten hospitals across Scotland, including 48,282 consecutive patients with suspected acute coronary syndrome. The diagnosis was adjudicated according to the Fourth Universal Definition of Myocardial Infarction. In patients with type 2 myocardial infarction, we prospectively adjudicated the cause for supply demand imbalance. Linkage of electronic healthcare records was used to track investigation, treatments and clinical outcomes. We used the Kaplan-Meier method, the log rank test and cox regression models adjusted for age, sex, renal function and co-morbidities to evaluate the risk of future all-cause mortality between categories.Results We identified 1,121 patients with type 2 myocardial infarction (age 74¬ ± 14, 55% female). At one year, death from any cause occurred in 23% (258/1,121) of patients. The most common reason for supply-demand imbalance was tachyarrhythmia in 55% (616/1,121), followed by hypoxaemia in 20% (219/1,121) of patients. Tachyarrhythmia was associated with reduced future risk of all-cause mortality (adjusted HR 0.69, 95%CI 0.43-1.09), similar to those with type 1 myocardial infarction. Comparatively, patients with hypoxaemia appeared at highest risk (adjusted HR 1.75, 95%CI 1.09-2.80). Conclusion The mechanism of myocardial oxygen supplydemand imbalance is associated with future prognosis, and should be considered when risk stratifying patients with type 2 myocardial infarction.
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