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Table 3 Summary of the effects of SGLT-2 inhibitors on cardiovascular function in animal models

From: Potential mechanisms responsible for cardioprotective effects of sodium–glucose co-transporter 2 inhibitors

Animal species Model Drug/dose/route Major findings Interpretation References
Wistar rats Streptozotocin-induced diabetic cardiomyopathy Empagliflozin (30 or 10 mg/kg/days)/PO/8 weeks ↑ ESP, + dp/dt and − dp/dt
↓ EDP
Empagliflozin improved LV function in streptozotocin-induced diabetic cardiomyopathy rats [62]
SHR/NDmcr-cp (+/+) rats Prediabetes/metabolic syndrome 0.03% empagliflozin/diet/7 weeks ↔ HR, SBP, DBP, locomotor activity, LF-SBP, sBRG and LF/HF ratio of PI Empagliflozin did not have effect on heart rate, blood pressure, sympathetic activity, or baroreceptor function in genetic prediabetic metabolic syndrome rats [57]
db/db mice Diabetes/obesity (diastolic dysfunction and LVH) Empagliflozin (10 mg/kg/days)/PO/5 weeks ↑ Septal wall motion
↓ CO, SV, LV filling pressure
↔ EF, FS
Empagliflozin improved septal wall motion and LV filling pressure in db/db mice [59]
db/db mice Diabetes/obesity (diastolic dysfunction and LVH) 0.03% empagliflozin/diet/10 weeks ↓ Impairment of vascular endothelium-dependent relaxation in thoracic aortas Empagliflozin attenuated vascular dilating dysfunction in db/db mice [58]
ob/ob mice T2DM/obesity (LV diastolic dysfunctions) Empagliflozin (10 mg/kg/days)/PO/6 weeks ↓ E wave, E wave deceleration time, Tau, EDPVR
↔ HR, EF, FS and ESPVR
Empagliflozin improved LV diastolic function but not systolic function in ob/ob mice [60]
BTBR ob/ob mice T2DM Dapagliflozin (1 mg/kg/days)/PO/8 weeks ↓ ESV, EDV, IVSs, IVSd
↑ EF, FS
↔ HR
Dapagliflozin improved LV function in BTBR ob/ob mice [63]
Seipin knockout (SKO) mice Diabetic lipodystrophic cardiomyopathy Dapagliflozin (1 mg/kg/days)/PO/8 weeks ↑ E/A ratio and EF
↓ IVRT, DT and EDWT
↔ EDV
Dapagliflozin improved both systolic and diastolic LV function in SKO mouse [69]
Rats High fat diet induced obese-insulin resistance for 4 weeks then I/R injury by LAD ligation Dapagliflozin (1 mg/kg/days)/PO/4 weeks Before I/R injury
↑ E/A ratio and EF
↓ HR, IVRT, DT and EDWT
During I/R injury
↑ Time to 1st VT/VF onset
↓ Arrhythmia score
↑ Gap junction protein connexin 43 expression
↔ Number of VT/VF and VT/VF incidence
↑ ESP, SV, EF and SW
↓ HR, EDP, ESV and EDV
Dapagliflozin improved both systolic and diastolic LV function and heart rate variability in pre-diabetic rats
Dapagliflozin prevented cardiac arrhythmia in pre-diabetic rats with cardiac I/R injury
[64]
Wistar rats MI by LAD ligation in rats Dapagliflozin (0.1 mg/kg/days)/PO/Start after 1-day infarction for 4 weeks ↑ Maximal rate of LV + dP/dt and − dP/dt Dapagliflozin improved cardiac function during post-infarction remodeling in rats [65]
  1. SGLT-2 sodium–glucose co-transporter 2, PO per oral, ESP end-systolic pressure, EDP end-diastolic pressure, + dp/dt maximal ascending rate of left ventricular pressure, − dp/dt maximal descending rate of left ventricular pressure, LV left ventricular, HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, LF low frequency, sBRG spontaneous baroreceptor reflex gain, HF high frequency, PI pulse interval, LVH left ventricular hypertrophy, CO cardiac output, SV stroke volume, EF ejection fraction, FS fractional shortening, T2DM type 2 diabetic mellitus, E wave mitral inflow peak velocity, Tau time constant for isovolumic relaxation, ESPVR end-systolic pressure–volume relationship, EDPVR end-diastolic pressure–volume relationship, ESV end-systolic volume, EDV end-diastolic volume, IVSs interventricular septal thickness in systole, IVSd interventricular septal thickness in diastole, E/A early/late diastolic, IVRT isovolumic relaxation time, DT deceleration time, EDWT end diastolic wall thickness, I/R ischemic/reperfusion, LAD left anterior descending artery, VT ventricular tachycardia, VF ventricular fibrillation, SW stroke work, MI myocardial infarction