Hyperglycemic exacerbation of myocardial infarction through SGLT1 - a glucose paradox

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.