GLP-1 vasodilatation in humans with coronary artery disease is not adenosine mediated.

BACKGROUND: Incretin therapies appear to provide cardioprotection and improve cardiovascular outcomes in patients with diabetes, but the mechanism of this effect remains elusive. We have previously shown that glucagon-like peptide (GLP)-1 is a coronary vasodilator and we sought to investigate if this is an adenosine-mediated effect. METHODS: We recruited 41 patients having percutaneous coronary intervention (PCI) for stable angina and allocated them into four groups administering a specific study-related infusion following successful PCI: GLP-1 infusion (Group G) (n = 10); Placebo, normal saline infusion (Group P) (n = 11); GLP-1 + Theophylline infusion (Group GT) (n = 10); and Theophylline infusion (Group T) (n = 10). A pressure wire assessment of coronary distal pressure and flow velocity (thermodilution transit time-Tmn) at rest and hyperaemia was performed after PCI and repeated following the study infusion to derive basal and index of microvascular resistance (BMR and IMR). RESULTS: There were no significant differences in the demographics of patients recruited to our study. Most of the patients were not diabetic. GLP-1 caused significant reduction of resting Tmn that was not attenuated by theophylline: mean delta Tmn (SD) group G - 0.23 s (0.27) versus group GT - 0.18 s (0.37), p = 0.65. Theophylline alone (group T) did not significantly alter resting flow velocity compared to group GT: delta Tmn in group T 0.04 s (0.15), p = 0.30. The resulting decrease in BMR observed in group G persisted in group GT: - 20.83 mmHg s (24.54 vs. - 21.20 mmHg s (30.41), p = 0.97. GLP-1 did not increase circulating adenosine levels in group GT more than group T: delta median adenosine - 2.0 ng/ml (- 117.1, 14.8) versus - 0.5 ng/ml (- 19.6, 9.4); p = 0.60. CONCLUSION: The vasodilatory effect of GLP-1 is not abolished by theophylline and GLP-1 does not increase adenosine levels, indicating an adenosine-independent mechanism of GLP-1 coronary vasodilatation. TRIAL REGISTRATION: The local research ethics committee approved the study (National Research Ethics Service-NRES Committee, East of England): REC reference 14/EE/0018. The study was performed according to institutional guidelines, was registered on http://www.clinicaltrials.gov (unique identifier: NCT03502083) and the study conformed to the principles outlined in the Declaration of Helsinki.

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

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.

Glucagon-like peptide-1 protects against ischemic left ventricular dysfunction during hyperglycemia in patients with coronary artery disease and type 2 diabetes mellitus.

BACKGROUND: Enhancement of myocardial glucose uptake may reduce fatty acid oxidation and improve tolerance to ischemia. Hyperglycemia, in association with hyperinsulinemia, stimulates this metabolic change but may have deleterious effects on left ventricular (LV) function. The incretin hormone, glucagon-like peptide-1 (GLP-1), also has favorable cardiovascular effects, and has emerged as an alternative method of altering myocardial substrate utilization. In patients with coronary artery disease (CAD), we investigated: (1) the effect of a hyperinsulinemic hyperglycemic clamp (HHC) on myocardial performance during dobutamine stress echocardiography (DSE), and (2) whether an infusion of GLP-1(7-36) at the time of HHC protects against ischemic LV dysfunction during DSE in patients with type 2 diabetes mellitus (T2DM). METHODS: In study 1, twelve patients underwent two DSEs with tissue Doppler imaging (TDI)-one during the steady-state phase of a HHC. In study 2, ten patients with T2DM underwent two DSEs with TDI during the steady-state phase of a HHC. GLP-1(7-36) was infused intravenously at 1.2 pmol/kg/min during one of the scans. In both studies, global LV function was assessed by ejection fraction and mitral annular systolic velocity, and regional wall LV function was assessed using peak systolic velocity, strain and strain rate from 12 paired non-apical segments. RESULTS: In study 1, the HHC (compared with control) increased glucose (13.0 ± 1.9 versus 4.8 ± 0.5 mmol/l, p < 0.0001) and insulin (1,212 ± 514 versus 114 ± 47 pmol/l, p = 0.01) concentrations, and reduced FFA levels (249 ± 175 versus 1,001 ± 333 µmol/l, p < 0.0001), but had no net effect on either global or regional LV function. In study 2, GLP-1 enhanced both global (ejection fraction, 77.5 ± 5.0 versus 71.3 ± 4.3%, p = 0.004) and regional (peak systolic strain -18.1 ± 6.6 versus -15.5 ± 5.4%, p < 0.0001) myocardial performance at peak stress and at 30 min recovery. These effects were predominantly driven by a reduction in contractile dysfunction in regions subject to demand ischemia. CONCLUSIONS: In patients with CAD, hyperinsulinemic hyperglycemia has a neutral effect on LV function during DSE. However, GLP-1 at the time of hyperglycemia improves myocardial tolerance to demand ischemia in patients with T2DM. TRIAL REGISTRATION: http://www.isrctn.org . Unique identifier ISRCTN69686930.

Optimising cardioprotection during myocardial ischaemia: targeting potential intracellular pathways with glucagon-like peptide-1.

Coronary heart disease and type-2 diabetes are both major global health burdens associated with an increased risk of myocardial infarction (MI). Following MI, ischaemia-reperfusion injury (IRI) remains a significant contributor to myocardial injury at the cellular level. Research has focussed on identifying a strategy or intervention to minimise IRI to optimise reperfusion therapy, with the aim of delivering a superior clinical outcome. The incretin hormone glucagon-like peptide-1, already an established basis for the treatment of type-2 diabetes, also has the potential to protect against IRI. We explain the physiology and cellular processes involved in IRI, and the intracellular pathways activated by GLP-1, which could intercept IRI and deliver cardioprotection. The review also examines the current preclinical and clinical evidence for GLP-1 in cardioprotection and future directions for research as we look for an effective adjunctive treatment to minimise IRI.

Glucagon-Like Peptide-1-Mediated Cardioprotection Does Not Reduce Right Ventricular Stunning and Cumulative Ischemic Dysfunction After Coronary Balloon Occlusion.

Stunning and cumulative ischemic dysfunction occur in the left ventricle with coronary balloon occlusion. Glucagon-like peptide (GLP)-1 protects the left ventricle against this dysfunction. This study used a conductance catheter method to evaluate whether the right ventricle (RV) developed similar dysfunction during right coronary artery balloon occlusion and whether GLP-1 was protective. In this study, the RV underwent significant stunning and cumulative ischemic dysfunction with right coronary artery balloon occlusion. However, GLP-1 did not protect the RV against this dysfunction when infused after balloon occlusion.

Effects of Acute GLP-1 Infusion on Pulmonary and Systemic Hemodynamics in Patients With Heart Failure: A Pilot Study.

PURPOSE: Cardiovascular-safety studies assessing glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have provided inconsistent data on the risk for developing heart failure. Animal studies have shown that GLP-1 is a vasodilator; if confirmed in humans, this may ameliorate heart failure symptoms. METHODS: In a single-center, observational pilot study, we recruited 10 patients with advanced heart failure undergoing right heart catheterization, and we recorded pulmonary hemodynamic measures, including cardiac output calculated by thermodilution and the indirect Fick method before and after a 15-minute continuous infusion of native GLP-1 (7-36) NH2. FINDINGS: There was a neutral effect of GLP-1 on all pressure and hemodynamics indices as derived by cardiac output calculated by thermodilution. However, there was a small but consistent reduction in cardiac output as calculated by the indirect Fick method after GLP-1 infusion (baseline, 4.0 [1.1] L/min vs GLP-1, 3.6 [0.9] L/min; P = 0.003), driven by a consistent reduction in mixed venous oxygen saturation after GLP-1 infusion (baseline, 62.2% [7.0%] vs GLP-1, 59.3% [6.8%]; P < 0.001), whereas arterial saturation remained constant (baseline, 96.8% [3.3%] vs GLP-1, 97.0% [3.2%]; P = 0.34). This resulted in an increase in systemic vascular resistance by Fick (baseline, 1285 [228] dyn · s/cm5 vs GLP-1, 1562 [247] dyn · s/cm5; P = 0.001). IMPLICATIONS: Acute infusion of GLP-1 has a neutral hemodynamic effect, when assessed by thermodilution, in patients with heart failure. However, GLP-1 reduces mixed venous oxygen saturation. ClinicalTrials.gov identifier: NCT02129179.

GLP-1 Is a Coronary Artery Vasodilator in Humans.

Background The mechanism underlying the beneficial cardiovascular effects of the incretin GLP-1 (glucagon-like peptide 1) and its analogues in humans is elusive. We hypothesized that activating receptors located on vascular smooth muscle cells to induce either peripheral or coronary vasodilatation mediates the cardiovascular effect of GLP -1. Methods and Results Ten stable patients with angina awaiting left anterior descending artery stenting underwent forearm blood flow measurement using forearm plethysmography and post-percutaneous coronary intervention coronary blood flow measurement using a pressure-flow wire before and after peripheral GLP -1 administration. Coronary sinus and artery bloods were sampled for GLP -1 levels. A further 11 control patients received saline rather than GLP -1 in the coronary blood flow protocol. GLP -1 receptor (GLP-1R) expression was assessed by immunohistochemistry using a specific GLP -1R monoclonal antibody in human tissue to inform the physiological studies. There was no effect of GLP -1 on absolute forearm blood flow or forearm blood flow ratio after GLP -1, systemic hemodynamics were not affected, and no binding of GLP -1R monoclonal antibody was detected in vascular tissue. GLP -1 reduced resting coronary transit time (mean [ SD ], 0.87 [0.39] versus 0.63 [0.27] seconds; P=0.02) and basal microcirculatory resistance (mean [ SD ], 76.3 [37.9] versus 55.4 [30.4] mm Hg/s; P=0.02), whereas in controls, there was an increase in transit time (mean [SD], 0.48 [0.24] versus 0.83 [0.41] seconds; P<0.001) and basal microcirculatory resistance (mean [SD], 45.9 [34.7] versus 66.7 [37.2] mm Hg/s; P=0.02). GLP -1R monoclonal antibody binding was confirmed in ventricular tissue but not in vascular tissue, and transmyocardial GLP -1 extraction was observed. Conclusions GLP -1 causes coronary microvascular dilation and increased flow but does not influence peripheral tone. GLP -1R immunohistochemistry suggests that GLP -1 coronary vasodilatation is indirectly mediated by ventricular-coronary cross talk.

Glucagon-Like Peptide-1: A Promising Agent for Cardioprotection During Myocardial Ischemia.

Glucagon-like peptide-1-(7-36) amide (GLP-1) is a human incretin hormone responsible for the release of insulin in response to food. Pre-clinical and human physiological studies have demonstrated cardioprotection from ischemia-reperfusion injury. It can reduce infarct size, ischemic left ventricular dysfunction, and myocardial stunning. GLP-1 receptor agonists have also been shown to reduce infarct size in myocardial infarction. The mechanism through which this protection occurs is uncertain but may include hijacking the subcellular pathways of ischemic preconditioning, modulation of myocardial metabolism, and hemodynamic effects including peripheral, pulmonary, and coronary vasodilatation. This review will assess the evidence for each of these mechanisms in turn. Challenges remain in successfully translating cardioprotective interventions from bench-to-bedside. The window of cardioprotection is short and timing of cardioprotection in the appropriate clinical setting is critically important. We will emphasize the need for high-quality, well-designed research to evaluate GLP-1 as a cardioprotective agent for use in real-world practice.

Pre-treatment with glucagon-like Peptide-1 protects against ischemic left ventricular dysfunction and stunning without a detected difference in myocardial substrate utilization.

OBJECTIVES: This study sought to determine whether pre-treatment with intravenous glucagon-like peptide-1 (GLP-1)(7-36) amide could alter myocardial glucose use and protect the heart against ischemic left ventricular (LV) dysfunction during percutaneous coronary intervention. BACKGROUND: GLP-1 has been shown to have favorable cardioprotective effects, but its mechanisms of action remain unclear. METHODS: Twenty patients with preserved LV function and single-vessel left anterior descending coronary artery disease undergoing elective percutaneous coronary intervention were studied. A conductance catheter was placed into the LV, and pressure-volume loops were recorded at baseline, during 1-min low-pressure balloon occlusion (BO), and at 30-min recovery. Patients were randomized to receive an infusion of either GLP-1(7-36) amide at 1.2 pmol/kg/min or saline immediately after baseline measurements. Simultaneous coronary artery and coronary sinus blood sampling was performed at baseline and after BO to assess transmyocardial glucose concentration gradients. RESULTS: BO caused both ischemic LV dysfunction and stunning in the control group but not in the GLP-1 group. Compared with control subjects, the GLP-1 group had a smaller reduction in LV performance during BO (delta dP/dTmax, -4.3 vs. -19.0%, p = 0.02; delta stroke volume, -7.8 vs. -26.4%, p = 0.05), and improved LV performance at 30-min recovery. There was no difference in transmyocardial glucose concentration gradients between the 2 groups. CONCLUSIONS: Pre-treatment with GLP-1(7-36) amide protects the heart against ischemic LV dysfunction and improves the recovery of function during reperfusion. This occurs without a detected change in myocardial glucose extraction and may indicate a mechanism of action independent of an effect on cardiac substrate use. (Effect of Glucgon-Like-Peptide-1 [GLP-1] on Left Ventricular Function During Percutaneous Coronary Intervention [PCI]; ISRCTN77442023).