Mohammed Ali Azam1, Praloy Chakraborty1, Daoyuan Si1, BeiBei Du1, Stéphane Massé1, Patrick F H Lai1, Andrew C T Ha2, Kumaraswamy Nanthakumar3. 1. The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Canada. 2. The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Canada; Toronto General Hospital, Canada. 3. The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Canada. Electronic address: kumar.nanthakumar@uhn.ca.
Abstract
BACKGROUND: Empagliflozin (EMPA) reduces heart failure hospitalization and mortality. The benefit in terms of ventricular arrhythmia and contractility has not been explored. OBJECTIVE: To determine the direct effects of EMPA on ventricular arrhythmia and cardiac contractility in an ex-vivo model of global ischemia-reperfusion (I/R). METHODS: Langendorff-perfused rabbit hearts were subjected to 30 min of complete perfusion arrest and reperfusion. Either EMPA (1 μM) or normal saline (controls) was then infused into the perfusate in a randomized fashion. Ten minutes following drug infusion, calcium imaging was performed. At the end of each experiment, the heart was electrically stimulated 5 times to assess the inducibility of ventricular fibrillation (VF). In a separate series of experiments, left ventricular (LV) pressure and epicardial NADH fluorescence were simultaneously recorded. LV specimens were then collected for western blotting. RESULTS: Post-ischemia, EMPA treatment was associated with reduction in the induction of VF >10s (rate of induction: 16.7 ± 3.3% vs. 60 ± 8.7% in control hearts, p = 0.003), improvement of LV developed pressure (LVDP; 68.10 ± 9.02% vs. 47.61 ± 5.15% in controls, p = 0.03) and reduction of NADH fluorescence (87.42 ± 2.79% vs. 112.88 ± 2.27% in control hearts, p = 0.04) along with an increase in NAD+/NADH ratio (2.75 ± 0.55 vs. 1.09 ± 0.32 in the control group, p = 0.04) A higher calcium amplitude alternans threshold was also observed with EMPA-treatment (5.42 ± 0.1 Hz vs. 4.75 ± 0.1 Hz in controls, p = 0.006). Sodium-glucose co-transporter-2 (SGLT2) expression was not detected in LV tissues. CONCLUSIONS: EMPA treatment reduced ventricular arrhythmia vulnerability and mitigated contractile dysfunction in the global I/R model while improving calcium cycling and mitochondrial redox by SGLT2-independent mechanisms.
BACKGROUND:Empagliflozin (EMPA) reduces heart failure hospitalization and mortality. The benefit in terms of ventricular arrhythmia and contractility has not been explored. OBJECTIVE: To determine the direct effects of EMPA on ventricular arrhythmia and cardiac contractility in an ex-vivo model of global ischemia-reperfusion (I/R). METHODS: Langendorff-perfused rabbit hearts were subjected to 30 min of complete perfusion arrest and reperfusion. Either EMPA (1 μM) or normal saline (controls) was then infused into the perfusate in a randomized fashion. Ten minutes following drug infusion, calcium imaging was performed. At the end of each experiment, the heart was electrically stimulated 5 times to assess the inducibility of ventricular fibrillation (VF). In a separate series of experiments, left ventricular (LV) pressure and epicardial NADH fluorescence were simultaneously recorded. LV specimens were then collected for western blotting. RESULTS: Post-ischemia, EMPA treatment was associated with reduction in the induction of VF >10s (rate of induction: 16.7 ± 3.3% vs. 60 ± 8.7% in control hearts, p = 0.003), improvement of LV developed pressure (LVDP; 68.10 ± 9.02% vs. 47.61 ± 5.15% in controls, p = 0.03) and reduction of NADH fluorescence (87.42 ± 2.79% vs. 112.88 ± 2.27% in control hearts, p = 0.04) along with an increase in NAD+/NADH ratio (2.75 ± 0.55 vs. 1.09 ± 0.32 in the control group, p = 0.04) A higher calcium amplitude alternans threshold was also observed with EMPA-treatment (5.42 ± 0.1 Hz vs. 4.75 ± 0.1 Hz in controls, p = 0.006). Sodium-glucose co-transporter-2 (SGLT2) expression was not detected in LV tissues. CONCLUSIONS:EMPA treatment reduced ventricular arrhythmia vulnerability and mitigated contractile dysfunction in the global I/R model while improving calcium cycling and mitochondrial redox by SGLT2-independent mechanisms.
Authors: Mohammed Ali Azam; Praloy Chakraborty; Mahmoud M Bokhari; Keith Dadson; Beibei Du; Stéphane Massé; Daoyuan Si; Ahmed Niri; Arjun K Aggarwal; Patrick F H Lai; Sheila Riazi; Filio Billia; Kumaraswamy Nanthakumar Journal: Heart Rhythm O2 Date: 2021-12-17
Authors: James P Curtain; Kieran F Docherty; Pardeep S Jhund; Mark C Petrie; Silvio E Inzucchi; Lars Køber; Mikhail N Kosiborod; Felipe A Martinez; Piotr Ponikowski; Marc S Sabatine; Olof Bengtsson; Anna Maria Langkilde; Mikaela Sjöstrand; Scott D Solomon; John J V McMurray Journal: Eur Heart J Date: 2021-09-21 Impact factor: 29.983
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