Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies

Joel P Giblett, Richard G Axell, Paul A White, Sophie J Clarke, Liam McCormick, Philip A Read, Johannes Reinhold, Adam J Brown, Michael O'Sullivan, Nick E J West, David P Dutka, Stephen P Hoole, Joel P Giblett, Richard G Axell, Paul A White, Sophie J Clarke, Liam McCormick, Philip A Read, Johannes Reinhold, Adam J Brown, Michael O'Sullivan, Nick E J West, David P Dutka, Stephen P Hoole

Abstract

Background: Glucagon-like peptide-1 (7-36) amide (GLP-1) protects against stunning and cumulative left ventricular dysfunction in humans. The mechanism remains uncertain but GLP-1 may act by opening mitochondrial K-ATP channels in a similar fashion to ischemic conditioning. We investigated whether blockade of K-ATP channels with glibenclamide abrogated the protective effect of GLP-1 in humans.

Methods: Thirty-two non-diabetic patients awaiting stenting of the left anterior descending artery (LAD) were allocated into 4 groups (control, glibenclamide, GLP-1, and GLP-1 + glibenclamide). Glibenclamide was given orally prior to the procedure. A left ventricular conductance catheter recorded pressure-volume loops during a 1-min low-pressure balloon occlusion (BO1) of the LAD. GLP-1 or saline was then infused for 30-min followed by a further 1-min balloon occlusion (BO2). In a non-invasive study, 10 non-diabetic patients were randomized to receive two dobutamine stress echocardiograms (DSE) during GLP-1 infusion with or without oral glibenclamide pretreatment.

Results: GLP-1 prevented stunning even with glibenclamide pretreatment; the Δ % dP/dtmax 30-min post-BO1 normalized to baseline after GLP-1: 0.3 ± 6.8 % (p = 0.02) and GLP-1 + glibenclamide: -0.8 ± 9.0 % (p = 0.04) compared to control: -11.5 ± 10.0 %. GLP-1 also reduced cumulative stunning after BO2: -12.8 ± 10.5 % (p = 0.02) as did GLP-1 + glibenclamide: -14.9 ± 9.2 % (p = 0.02) compared to control: -25.7 ± 9.6 %. Glibenclamide alone was no different to control. Glibenclamide pretreatment did not affect global or regional systolic function after GLP-1 at peak DSE stress (EF 74.6 ± 6.4 vs. 74.0 ± 8.0, p = 0.76) or recovery (EF 61.9 ± 5.7 vs. 61.4 ± 5.6, p = 0.74).

Conclusions: Glibenclamide pretreatment does not abrogate the protective effect of GLP-1 in human models of non-lethal myocardial ischemia. Trial registration Clinicaltrials.gov Unique Identifier: NCT02128022.

Keywords: Cardioprotection; Glucagon-like peptide-1; Ischemia–reperfusion injury; KATP.

Figures

Fig. 1
Fig. 1
Structure of supply and demand protocols. a Timeline for the supply ischemia protocol. Blood tests were taken immediately before the two balloon occlusions. GLP-1 was administered until BO2 was complete. b The study timeline for the demand ischemia protocol
Fig. 2
Fig. 2
Examples of methodology. a Conductance catheter in position in the left ventricle during an injection of contrast into the left coronary artery. The proximal LAD lesion can be seen. b Pressure–volume loops generated at baseline (blue) and during occlusion of the LAD (red). c Dobutamine stress echo at peak stress. Strain rate is shown to the right with the peak systolic strain rate the most negative point between aortic valve opening and closure
Fig. 3
Fig. 3
Systolic function (ΔdP/dtmax) in supply ischemia protocol. Mean ± SEM. There were no statistically significant differences between groups at BO1. At BL2, dP/dtmax for GLP-1 was significantly improved compared to control (p = 0.02) and compared to glibenclamide alone (p < 0.01). This difference was maintained for comparison with control at BO2 (p = 0.02) and was numerically better than glibenclamide at BO2 (p = 0.12). dP/dtmax for GLP-1 + glibenclamide was significantly improved at BL2 compared to control (p = 0.02) and glibenclamide alone (p = 0.03). Again this difference was maintained for comparison with control at BO2 (p = 0.02) and trended towards improvement for glibenclamide alone at BO2 (p = 0.14). There was no statistically significant difference between GLP-1 treated groups, nor any difference between the control and glibenclamide only groups, at any timepoint
Fig. 4
Fig. 4
Diastolic function (ΔdP/dtmin) in supply ischemia protocol. Mean ± SEM. There were no statistically significant differences between groups at BO1. At BL2, dP/dtmin for GLP-1 was significantly improved compared to control (p < 0.01) and numerically better than glibenclamide alone (p = 0.07). The difference between GLP-1 vs. control was maintained at BO2 (p = 0.01). At BL2, dP/dtmin for GLP-1 + glibenclamide was again significantly improved compared to control (p < 0.01), and numerically better than glibenclamide alone (p = 0.15). These differences persisted for BO2 (p < 0.01 and 0.06 respectively). There was no statistically significant difference between GLP-1 treated groups, nor any difference between the control and glibenclamide only groups, at any timepoint
Fig. 5
Fig. 5
Systolic function in demand ischemia protocol. Mean ± SEM. Changes in global and regional systolic function at baseline, peak stress and 30-min recovery. There are no statistically significant differences between the two studies at any timepoint. a Ejection fraction. b Mitral annular systolic velocity. c Peak systolic tissue velocity (Vs). d Peak systolic strain (SI). e Peak systolic strain rate (SRI)

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