Cardiac Response to SGLT2 Inhibitors is Proportional to the Severity of Coronary Ischemia

Sodium–glucose cotransporter 2 inhibitors (SGLT2i) reduce heart failure hospitalization and cardiovascular death, but the mechanism of cardioprotection remains unclear. Our lab has identified lusitropy associated enhancements to cardiac efficiency during ischemia as a candidate driver of benefit. Because mitochondria are central to bioenergetics and redox balance, we tested whether graded ischemia produces proportional dysfunction at the mechanical and mitochondrial levels, and whether SGLT2i attenuate these effects. Domestic swine were randomized to control, canagliflozin, or empagliflozin. Graded left circumflex ischemia was induced using a reversible snare occluder, targeting ~normal flow, –20%, –40%, –60%, –80%, and total occlusion. At each stage, coronary flow, pressure–volume loops, myocardial oxygen consumption, aortic pressure, and ECG were recorded. After humane euthanasia, myocardial biopsies were collected from ischemic and normally perfused territories and mitochondrial respiration assessed by high-resolution respirometry. Stroke work declined with graded ischemia in control animals but was preserved with canagliflozin across severities; empagliflozin showed similar but less consistent trends. Ischemia produced proportional decrements in mitochondrial function, reducing ATP-generating capacity, coupling efficiency (respiratory control index, S3/S4), reserve capacity (S3-S1), and the ability to shift from leak to ATP production (S3/S2), while increasing proton leak (S4/S2) (p ≤ 0.05). Both SGLT2i showed reproducible trends toward preserving mitochondrial energetics, with empagliflozin generally stronger. Graded ischemia impaired ventricular performance and mitochondrial respiration, validating this model for mechanistic testing. SGLT2i preserved stroke work and showed consistent trends toward mitochondrial protection, supporting mitochondria as a candidate mechanism for clinical cardioprotection. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.