Reply: Glucagon-like peptide-1 mediates cardioprotection by remote ischaemic conditioning

We read with interest the Letter by Drs Giblett and Hoole in response to our research article ‘Glucagon-Like Peptide-1 (GLP-1) Mediates Cardioprotection by Remote Ischaemic Conditioning’.1 We thank Drs Giblett and Hoole for their interest in our work and provide our responses to the critical comments raised. First, we believe that it is not entirely appropriate to compare the effects of exogenous application of native GLP-1 or GLP-1 receptor (GLP-1R) agonists with the effects induced by remote ischaemic conditioning (RIc). The efficacy of RIc in protecting against left ventricular dysfunction and myocardial stunning may be compromised by the study design and/or inability of a significant proportion of patients to recruit vagal activity, which appears to be critically important for RIc cardioprotection.2,3 We reported that in rats vagotomy blocks RIc cardioprotection, whereas cardioprotection induced by GLP-1R agonist Ex-4 is not affected. In recent ERICCA4 and RIPHeart5 trials (both failed to demonstrate RIc benefit) the majority of patients received propofol, an anaesthetic agent known to suppress autonomic reflex pathways. As we reasoned in our earlier publications6,7 and recently reported supporting evidence,8 parasympathetic tone decreases with age and could be severely diminished or even absent in many disease states, perhaps rendering many patients unable to recruit vagal/GLP-1R-mediated mechanisms.