Neuron-Specific Enolase and Matrix Metalloproteinase 9 Signal Perioperative Silent Brain Infarction During or After Transcatheter Aortic Valve Implantation

Fanning, Jonathon P.; Hoe, Louise E. See; Passmore, Margaret; Barnett, Adrian; Obonyo, Nchafatso G.; Millar, Jonathan; Wesley, Allan J.; Suen, Jacky Y.

doi:10.1016/j.amjcard.2018.10.022

Cited by 5 publications

(5 citation statements)

References 23 publications

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“…62 Likewise, cardiac interventions, such as transcatheter aortic valve implantation, can cause cerebrovascular complications. 63 We previously used a rat model of ischemic stroke to show that a single dose of Hi1a (2 ng/kg intracerebroventricular) dramatically reduced infarct size and improved neurologic and motor performance even when administered up to 8 hours after stroke onset. 33 No other drugs have been shown to provide significant protection beyond 4 hours after stroke onset.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia–Reperfusion Injury

et al. 2021

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Background: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the build-up of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6.0-6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly impacts cardiac function. Methods: We used genetic and pharmacological methods to investigate the role of acid sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole organ level. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and post-conditioning therapeutic agents. Results: Analysis of human complex trait genetics indicate that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using hiPSC-CMs in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacological inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction (MI) and two models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as pre- or post-conditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no impact on cardiac ion channels regulating baseline electromechanical coupling and physiological performance. Conclusions: Collectively, our data provide compelling evidence for a novel pharmacological strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia–Reperfusion Injury

et al. 2021

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“…No prior study as far as we know has investigated NFL levels in relation to TAVI, although one ongoing randomized clinical trial on TAVI has included change in NFL within 3 months as an outcome in their protocol (ClinicalTrials.gov NCT05145283). Other circulating biomarkers of neuroglial injury, such as neuron-specific enolase, glial fibrillary acidic protein, and S100 calcium-binding protein B, have been studied in relation to TAVI with conflicting results [3, 18–20]. This may be explained by difference in the timing of blood sample as the protein levels peak at different time points for different proteins.…”

Section: Discussionmentioning

confidence: 99%

“…gov NCT05145283). Other circulating biomarkers of neuroglial injury, such as neuron-specific enolase, glial fibrillary acidic protein, and S100 calcium-binding protein B, have been studied in relation to TAVI with conflicting results [3,[18][19][20]. This may be explained by difference in the timing of blood sample as the protein levels peak at different time points for different proteins.…”

Section: Plasma Nfl In Tavimentioning

confidence: 99%

Plasma Neurofilament Light Chain Is Elevated after Transcatheter Aortic Valve Implantation

Sjölin¹,

Christersson²,

James³

et al. 2023

Cardiology

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Introduction: Transcatheter aortic valve implantation (TAVI) is associated with a high incidence of new silent brain infarcts (SBI) on postprocedural neuroimaging. A venous blood sample reflecting neuronal damage following TAVI, could help identify patients with potential SBI. We aimed to investigate if a biochemical marker of neuronal injury, neurofilament light chain (NFL), is elevated after TAVI. Methods: In this observational study, NFL was measured in plasma from 31 patients before and after TAVI. Multivariable regression analysis was performed to investigate any effect of clinical and procedure related factors on differences in NFL levels before and after TAVI. Results: Samples were collected 41 (14-81) days before and 44 (35-59) days after TAVI, median (interquartile range, IQR). Median age was 81 (77-84) years, and 35% were female. No patient had any overt procedure related neurological complications. The geometric mean (95% confidence interval) of the NFL concentration was 30 (25-36) pg/ml before TAVI and 48 (39-61) pg/ml, after TAVI, P < 0.001. None of the included variables in the multiple linear regression model were statistically significantly associated with the difference in levels before and after TAVI. Conclusions: NFL levels in plasma were higher after TAVI as compared with levels before, with a mean increase of 60% (18 pg/ml). Further studies including neuroimaging and cognitive outcomes are needed to understand the potential value of measuring NFL in relation to TAVI. Trial registration: ClinicalTrials.gov NCT05629104.

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“…In general, there is a strong association and co-morbidity between stroke and cardiac arrest, with 88% of patients suffering some form of cardiovascular complication within 4 weeks of an ischemic stroke 58 . Likewise, cardiac interventions such as transcatheter aortic valve implantation (TAVI) can cause cerebrovascular complications 59 . We previously used a rat model of ischemic stroke to show that a single dose of Hi1a (2 ng/kg i.c.v) massively reduced infarct size and improved neurological and motor performance even when administered up to 8 h after stroke onset 32 .…”

Section: Discussionmentioning

confidence: 99%

Acid sensing ion channel 1a is a key mediator of cardiac ischemia-reperfusion injury

Scheuer

Saez

et al. 2019

Preprint

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Ischemia reperfusion injury (IRI) is one of the major risk factors associated with primary graft dysfunction, the leading cause of early mortality in heart transplant recipients. Here, we show that the proton-gated acid-sensing ion channel 1a (ASIC1a) plays a key role during cardiac ischemia and demonstrate that ASIC1a is a promising new target to improve the tolerance of cardiac tissue to IRI.Genetic ablation of ASIC1a leads to improved functional recovery following global myocardial IRI in ex vivo mouse hearts, and this effect can be recapitulated by therapeutic blockade of ASIC1a using specific and potent venom-derived pharmacological inhibitors. Using two models of donor heart procurement and storage, we show that ASIC1a inhibition yields improved post-IRI cardiac viability and function as a pre-or post-conditioning agent, with organ recovery equal to benchmark drugs including the sodium-hydrogen exchange inhibitor, zoniporide. Using human pluripotent stem cells, we show that ASIC1a inhibition improves cardiomyocyte viability under conditions of acidosis or ischemia in vitro. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors have no impact on cardiac electromechanical coupling and physiological performance.Consistent with a key role for ASIC1a in human cardiac ischemia, we used summary data from GWAS to show that polymorphisms in the ASIC1 genetic locus are strongly associated with susceptibility to cardiac ischemic injuries. Collectively, our data provide compelling evidence for a novel pharmacological strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of donor hearts exposed to myocardial ischemia. Significance StatementIschemia-reperfusion injury (IRI) is the primary reason for early allograft failure after heart transplantation. IRI is also implicated in the pathophysiology of diverse post-ischemic heart diseases that are a leading cause of morbidity and mortality worldwide. There are currently no drugs available to protect the heart from IRI. This study uses genetic approaches to demonstrate a novel role for ASIC1a in mediating the response of the heart to IRI. In addition, we identify venom-derived ASIC1a inhibitors as novel pharmacological therapeutics for cardiovascular medicine, in particular for the preservation of donor hearts destined for transplantation.

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Neuron-Specific Enolase and Matrix Metalloproteinase 9 Signal Perioperative Silent Brain Infarction During or After Transcatheter Aortic Valve Implantation

Cited by 5 publications

References 23 publications

Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia–Reperfusion Injury

Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia–Reperfusion Injury

Plasma Neurofilament Light Chain Is Elevated after Transcatheter Aortic Valve Implantation

Acid sensing ion channel 1a is a key mediator of cardiac ischemia-reperfusion injury

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