Inhibition of sodium-glucose cotransporter-2 preserves cardiac function during regional myocardial ischemia independent of alterations in myocardial substrate utilization

Abstract

The goal of the present study was to evaluate the effects of SGLT2i on cardiac contractile function, substrate utilization, and efficiency before and during regional myocardial ischemia/reperfusion injury in normal, metabolically healthy swine. Lean swine received placebo or canagliflozin (300 mg PO) 24 h prior to and the morning of an invasive physiologic study protocol. Hemodynamic and cardiac function measurements were obtained at baseline, during a 30-min complete occlusion of the circumflex coronary artery, and during a 2-h reperfusion period. Blood pressure, heart rate, coronary flow, and myocardial oxygen consumption were unaffected by canagliflozin treatment. Ventricular volumes remained unchanged in controls throughout the protocol. At the onset of ischemia, canagliflozin produced acute large increases in left ventricular end-diastolic and systolic volumes which returned to baseline with reperfusion. Canagliflozin-mediated increases in end-diastolic volume were directly associated with increases in stroke volume and stroke work relative to controls during ischemia. Canagliflozin also increased cardiac work efficiency during ischemia relative to control swine. No differences in myocardial uptake of glucose, lactate, free fatty acids or ketones, were noted between treatment groups at any time. In separate experiments using a longer 60 min coronary occlusion followed by 2 h of reperfusion, canagliflozin increased end-diastolic volume and stroke volume and significantly diminished myocardial infarct size relative to control swine. These data demonstrate that SGLT2i with canagliflozin preserves cardiac contractile function and efficiency during regional myocardial ischemia and provides ischemia protection independent of alterations in myocardial substrate utilization.

Keywords: Cardiac function; Fuel selection; Infarct; Myocardial ischemia; Pig; SGLT2 inhibition.

Fig. 1

qPCR for SGLT1 (a) and SGLT2 (b) in kidney (n = 5) vs. heart (n = 5) biopsies from domestic swine

Fig. 2

Effects of ischemia/reperfusion injury on mean blood pressure (a) and heart rate (b) in control (n = 7) and SGLT2i (canagliflozin)-treated (n = 8) swine

Fig. 3

Effect of ischemia/reperfusion injury on end-diastolic pressure (a), end-systolic volume (b), stroke volume(c) and cardiac output (d) in control (n = 7) and SGLT2i (canagliflozin)-treated (n = 8) swine. *P <0.05 vs. control (same timepoint), ^†P <0.05 vs. baseline (same treatment)

Fig. 4

Representative pressure–volume loops of average steady-state conditions at baseline and during regional myocardial ischemia in control (n = 7) (a) and SGLT2i (canagliflozin) (n = 8)-treated (b) swine. Relationship between stroke volume (c) and cardiac output (d) and end-diastolic volume during ischemia in control (n = 8) and SGLT2i (canagliflozin) (n = 7)-treated swine

Fig. 5

Effect of ischemia/reperfusion injury on cardiac stroke work (a), efficiency (b) in control (n = 7), and SGLT2i (canagliflozin)-treated (n = 8) swine. *P <0.05 vs. control (same timepoint)

Fig. 6

Effect of ischemia/reperfusion injury on myocardial uptake of glucose (a), lactate (b), ketones (c), and free fatty acids (FFA) d in control (n = 7) and SGLT2i (canagliflozin)-treated (n = 8) swine

Fig. 7

Images in a show representative transmural sections of left ventricular slices from control (n = 6) and canagliflozin (n = 6)-treated swine. Quantification of total infarct area relative to total left ventricular area is presented in b. *P <0.05 vs. control