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Title: The cardiovascular effect of GLP-1 in humans
Author: Clarke, Sophie
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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The incretin glucagon-like peptide-1 (GLP-1) abolishes post-ischemic left ventricular contractility (stunning) in humans but the mechanism remains elusive. I hypothesized that this effect is mediated by peripheral or coronary vasodilatation. A comprehensive assessment of the haemodynamic effects of GLP-1 in humans was made, in peripheral arteries using plethysmography, and in coronary arteries using invasive pressure and flow assessments during cardiac catherisation. I also evaluated transmyocardial extraction of GLP-1 and mapped the distribution of the GLP-1 receptor in the human cardiovascular system using immunohistochemistry with an extensively validated monoclonal antibody (mAb). There was no effect of GLP-1 on forearm blood flow, nor were systemic hemodynamics or cardiac output affected, and no binding of GLP-1R mAb was detected in vascular tissue. GLP-1 reduced resting coronary transit time (Tmn (s)) mean (SD): 0.87 (0.39) vs. 0.63 (0.27), p=0.02 and basal microcirculatory resistance (BMR (mmHgs)) mean (SD): 76.3 (37.9) vs. 55.4 (30.4) p=0.02, whereas in controls there was an increase in Tmn: 0.48 (0.24) vs.0.83 (0.41), p < 0.001 and BMR: 45.9 (34.7) vs. 66.7 (37.2), p=0.02. GLP-1 R mAb binding was confirmed in ventricular tissue and transmyocardial GLP-1 extraction was observed. Conclusion: GLP-1 causes coronary microvascular dilation and increased flow but does not influence peripheral tone. GLP-1 R immunohistochemistry suggests that GLP-1 coronary vasodilatation is indirectly mediated by a non-receptor mechanism.
Supervisor: Morrell, Nick ; Hoole, Stephen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: glucagon-like peptide-1 ; cardioprotection ; GLP-1 ; coronary haemodynamics