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.
0110 : Experimental cerebral ischemia in rats increases myocardial vulnerability to ischemia-reperfusion injury ex vivo
