Hurdles to Cardioprotection in the Critically Ill

Hoe, Louise E. See; Bartnikowski, Nicole; Wells, M.; Suen, Jacky Y.

doi:10.3390/ijms20153823

Cited by 6 publications

(7 citation statements)

References 367 publications

(469 reference statements)

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“…3 Globally, 1 in 5 people develop HF, with annual health care costs of $108 billion. 4,5 Heart transplantation remains the most effective treatment option for HF, 6,7 but 75% of potential donor hearts are discarded, many because of sensitivity of the donor heart to ischemic injury. 7 Myocardial sensitivity to ischemia–reperfusion injury (IRI) therefore remains a primary point of vulnerability underlying cardiovascular disease, which is the leading cause of morbidity and mortality worldwide.…”

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confidence: 99%

“…4,5 Heart transplantation remains the most effective treatment option for HF, 6,7 but 75% of potential donor hearts are discarded, many because of sensitivity of the donor heart to ischemic injury. 7 Myocardial sensitivity to ischemia–reperfusion injury (IRI) therefore remains a primary point of vulnerability underlying cardiovascular disease, which is the leading cause of morbidity and mortality worldwide. 1 Despite decades of preclinical therapeutic development, no drugs in clinical use block the acute injury response to cardiac ischemia.…”

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confidence: 99%

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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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confidence: 99%

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

et al. 2021

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“…Given that drug targets with genetic evidence of disease association are twice as likely to succeed in clinical trials and lead to approved drug candidates 47 , our GWAS analysis of the association between genetic variation in the ACCN1 locus and ischemic disease points towards the translational potential of ASIC1a-targeted therapies. Such therapies have the potential to impact a broad scope of clinical applications since myocardial IRI is evident in many cardiovascular complications such as acute MI, out-of-hospital cardiac arrest (OHCA), cardiopulmonary bypass, and heart preservation for transplantation 7 . Despite intensive research into therapies aimed at mitigating myocardial IRI in the context of acute MI, none have translated into clinical practice.…”

Section: Discussionmentioning

confidence: 99%

“…The viability of usable BD and DCD hearts, however, continues to be adversely affected by unavoidable injury to the heart that occurs during organ procurement and storage, as well as reperfusion injury in the recipient. Indeed, the relative risk of one-year morbidity is strongly correlated with organ ischemic time 7,61 . In general, primary graft dysfunction is a major risk for patients in the first 30 days after transplantation and accounts for 66% of patient deaths, of which 48% are due to IRI 62 .…”

Section: Discussionmentioning

confidence: 99%

“…Globally, 1 in 5 people develop HF, with annual healthcare costs of $108B 4,5 . Heart transplantation remains the most effective treatment option for HF 6,7 , but 75% of potential donor hearts are discarded, many due to sensitivity of the donor heart to ischemic injury 8 . Myocardial sensitivity to ischemia-reperfusion injury (IRI) therefore remains a primary point of vulnerability underlying cardiovascular disease, which is the leading cause of morbidity and mortality worldwide 9 .…”

Section: Introductionmentioning

confidence: 99%

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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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