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Neurotherapeutics : the Journal of the... Apr 2023When treating acute ischemic stroke patients in our daily clinical practice, we strive to achieve recanalization of the occluded blood vessel as fast as possible using... (Review)
Review
When treating acute ischemic stroke patients in our daily clinical practice, we strive to achieve recanalization of the occluded blood vessel as fast as possible using pharmacological thrombolysis and mechanical clot removal. However, successful recanalization does not equal successful reperfusion of the ischemic tissue due to mechanisms such as microvascular obstruction. Even if successful reperfusion is achieved, numerous other post-recanalization tissue damage mechanisms may impair patient outcomes, namely blood-brain barrier breakdown, reperfusion injury and excitotoxicity, late secondary changes, and post-infarction local and global brain atrophy. Several cerebroprotectants are currently evaluated as adjunctive treatments to pharmacological thrombolysis and mechanical clot removal, many of which interfere with post-recanalization tissue damage pathways. However, our current lack of knowledge about the prevalence and importance of the various post-recanalization tissue damage mechanisms makes it difficult to reliably identify the most promising cerebroprotectants and to design appropriate clinical trials to evaluate them. Serial human MRI studies with complementary animal studies in higher order primates could provide answers to these critical questions and should be first conducted to allow for adequate cerebroprotection trial design, which could accelerate the translation of cerebroprotective agents from bench to bedside to further improve patient outcomes.
Topics: Animals; Humans; Stroke; Ischemic Stroke; Reperfusion; Magnetic Resonance Imaging; Treatment Outcome; Brain Ischemia
PubMed: 37014594
DOI: 10.1007/s13311-023-01367-3 -
Lakartidningen Sep 2023
Topics: Humans; Stroke; Reperfusion
PubMed: 37671948
DOI: No ID Found -
Cardiovascular Research Dec 2023Empagliflozin (EMPA), a potent inhibitor of the renal sodium-glucose cotransporter 2 and an effective treatment for Type 2 diabetes, has been shown to have...
AIMS
Empagliflozin (EMPA), a potent inhibitor of the renal sodium-glucose cotransporter 2 and an effective treatment for Type 2 diabetes, has been shown to have cardioprotective effects, independent of improved glycaemic control. Several non-canonical mechanisms have been proposed to explain these cardiac effects, including increasing circulating ketone supply to the heart. This study aims to test whether EMPA directly alters cardiac ketone metabolism independent of supply.
METHODS AND RESULTS
The direct effects of EMPA on cardiac function and metabolomics were investigated in Langendorff rat heart perfused with buffer containing 5 mM glucose, 4 mM β-hydroxybutyrate (βHb) and 0.4 mM intralipid, subject to low flow ischaemia/reperfusion. Cardiac energetics were monitored in situ using 31P NMR spectroscopy. Steady-state 13C labelling was performed by switching 12C substrates for 13C1 glucose or 13C4 βHb and 13C incorporation into metabolites determined using 2D 1H-13C HSQC NMR spectroscopy. EMPA treatment improved left ventricular-developed pressure during ischaemia and reperfusion compared to vehicle-treated hearts. In EMPA-treated hearts, total adenosine triphosphate (ATP) and phosphocreatine (PCr) levels, and Gibbs free energy for ATP hydrolysis were significantly higher during ischaemia and reperfusion. EMPA treatment did not alter the incorporation of 13C from glucose into glycolytic products lactate or alanine neither during ischaemia nor reperfusion. In ischaemia, EMPA led to a decrease in 13C1 glucose incorporation and a concurrent increase in 13C4 βHb incorporation into tricarboxylic acid (TCA) cycle intermediates succinate, citrate, and glutamate. During reperfusion, the concentration of metabolites originating from 13C1 glucose was similar to vehicle but those originating from 13C4 βHb remained elevated in EMPA-treated hearts.
CONCLUSION
Our findings indicate that EMPA causes a switch in metabolism away from glucose oxidation towards increased ketone utilization in the rat heart, thereby improving function and energetics both during ischaemia and recovery during reperfusion. This preference of ketone utilization over glucose was observed under conditions of constant supply of substrate, suggesting that EMPA acts directly by modulating cardiac substrate preference, independent of substrate availability. The mechanisms underlying our findings are currently unknown, warranting further study.
Topics: Rats; Animals; Diabetes Mellitus, Type 2; Glucose; Adenosine Triphosphate; Ischemia; Reperfusion
PubMed: 37819017
DOI: 10.1093/cvr/cvad157 -
Stroke Dec 2023The Stroke Treatment Academic Industry Roundtable XII included a workshop to discuss the most promising approaches to improve outcome from acute stroke. The workshop... (Review)
Review
The Stroke Treatment Academic Industry Roundtable XII included a workshop to discuss the most promising approaches to improve outcome from acute stroke. The workshop brought together representatives from academia, industry, and government representatives. The discussion examined approaches in 4 epochs: pre-reperfusion, reperfusion, post-reperfusion, and access to acute stroke interventions. The participants identified areas of priority for developing new and existing treatments and approaches to improve stroke outcomes. Although many advances in acute stroke therapy have been achieved, more work is necessary for reperfusion therapies to benefit the most possible patients. Prioritization of promising approaches should help guide the use of resources and investigator efforts.
Topics: Humans; Brain Ischemia; Thrombolytic Therapy; Stroke; Thrombectomy; Reperfusion; Treatment Outcome
PubMed: 37886850
DOI: 10.1161/STROKEAHA.123.044279 -
Journal of the American College of... May 2023
Topics: Humans; Coronary Occlusion; Heparin; Platelet Aggregation Inhibitors; Reperfusion
PubMed: 37164526
DOI: 10.1016/j.jacc.2023.03.391 -
International Journal of Molecular... Dec 2022This Special Issue aims to highlight new avenues in the management of Ischemia/Reperfusion (I/R) injury [...].
This Special Issue aims to highlight new avenues in the management of Ischemia/Reperfusion (I/R) injury [...].
Topics: Humans; Reperfusion Injury; Ischemia; Reperfusion
PubMed: 36555508
DOI: 10.3390/ijms232415867 -
The Journal of Thoracic and... Feb 2021
Topics: Adsorption; Humans; Ischemia; Lung; Reperfusion; Reperfusion Injury
PubMed: 32107028
DOI: 10.1016/j.jtcvs.2019.12.010 -
Theranostics 2023Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating...
Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Renal tubule specific ELA knockout ( KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.
Topics: Mice; Animals; Microcirculation; Dinoprostone; Kidney; Acute Kidney Injury; Renal Insufficiency, Chronic; Reperfusion Injury; Ischemia; Peptide Hormones; Reperfusion
PubMed: 37351176
DOI: 10.7150/thno.84308 -
Journal of Cardiovascular Pharmacology... Nov 2021Cardiac reperfusion injury is a well-established outcome following treatment of acute myocardial infarction and other types of ischemic heart conditions. Numerous... (Review)
Review
Cardiac reperfusion injury is a well-established outcome following treatment of acute myocardial infarction and other types of ischemic heart conditions. Numerous cardioprotection protocols and therapies have been pursued with success in pre-clinical models. Unfortunately, there has been lack of successful large-scale clinical translation, perhaps in part due to the multiple pathways that reperfusion can contribute to cell death. The search continues for new cardioprotection protocols based on what has been learned from past results. One class of cardioprotection protocols that remain under active investigation is that of controlled reperfusion. This class consists of those approaches that modify, in a controlled manner, the content of the reperfusate or the mechanical properties of the reperfusate (e.g., pressure and flow). This review article first provides a basic overview of the primary pathways to cell death that have the potential to be addressed by various forms of controlled reperfusion, including no-reflow phenomenon, ion imbalances (particularly calcium overload), and oxidative stress. Descriptions of various controlled reperfusion approaches are described, along with summaries of both mechanistic and outcome-oriented studies at the pre-clinical and clinical phases. This review will constrain itself to approaches that modify endogenously-occurring blood components. These approaches include ischemic postconditioning, gentle reperfusion, controlled hypoxic reperfusion, controlled hyperoxic reperfusion, controlled acidotic reperfusion, and controlled ionic reperfusion. This review concludes with a discussion of the limitations of past approaches and how they point to potential directions of investigation for the future.
Topics: Humans; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Oxidative Stress
PubMed: 34534022
DOI: 10.1177/10742484211046674 -
Hellenic Journal of Cardiology : HJC =... 2019The management of ST-segment elevation myocardial infarction (STEMI) has evolved significantly over the last decades. STEMI treatment includes reperfusion therapy,... (Review)
Review
The management of ST-segment elevation myocardial infarction (STEMI) has evolved significantly over the last decades. STEMI treatment includes reperfusion therapy, ideally by primary percutaneous coronary intervention (pPCI), modern antithrombotic therapy and secondary prevention measures. Even though many areas in the management of STEMI are well studied and analyzed in the guidelines, there are still challenges and unanswered questions on how to improve outcomes. This review aims to offer an insight in areas that need to be explored.
Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Cyclosporine; Female; Humans; Hypothermia; Male; Middle Aged; Mitochondria, Heart; Myocardial Reperfusion; Percutaneous Coronary Intervention; Platelet Membrane Glycoproteins; Practice Guidelines as Topic; Purinergic P2Y Receptor Antagonists; ST Elevation Myocardial Infarction; Secondary Prevention; Thrombolytic Therapy; Time Factors; Treatment Outcome; Vasodilator Agents
PubMed: 30639352
DOI: 10.1016/j.hjc.2019.01.001