Abstract
dc:description.abstractThe 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.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2019
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Clarke, Sophie
- Advisors dc:contributor.advisor
-
- Morrell, Nick
- Hoole, Stephen
Subjects
dc:subject × 4Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.41479
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/294378