Bayliss Starling Prize Lecture 2023: Neuropeptide-Y being 'unsympathetic' to the broken hearted

Abstract

William Bayliss and Ernest Starling are not only famous as pioneers in cardiovascular physiology, but also responsible for the discovery of the first hormone (from the Greek 'excite or arouse'), the intestinal signalling molecule and neuropeptide secretin in 1902. Our research group focuses on neuropeptides and neuromodulators that influence cardiovascular autonomic control as potential biomarkers in disease and tractable targets for therapeutic intervention. Acute myocardial infarction (AMI) and chronic heart failure (CHF) result in high levels of cardiac sympathetic stimulation, which is a poor prognostic indicator. Although beta-blockers improve mortality in these conditions by preventing the action of the neurotransmitter noradrenaline, a substantial residual risk remains. Recently, we have identified the sympathetic co-transmitter neuropeptide-Y (NPY) as being released during AMI, leading to larger infarcts and life-threatening arrhythmia in both animal models and patients. Here, we discuss recently published data demonstrating that peripheral venous NPY levels are associated with heart failure hospitalisation and mortality after AMI, and all cause cardiovascular mortality in CHF, even when adjusting for known risk factors (including brain natriuretic peptide). We have investigated the mechanistic basis for these observations in human and rat stellate ganglia and cardiac tissue, manipulating NPY neurochemistry at the same time as using state-of-the-art imaging techniques, to establish the receptor pathways responsible for NPY signalling. We propose NPY as a new mechanistic biomarker in AMI and CHF patients and aim to determine whether specific NPY receptor blockers can prevent arrhythmia and attenuate the development of heart failure.

Keywords: arrhythmia; autonomic nervous system; coronary microvascular function; heart failure; neuropeptide Y; sympathetic nervous system; ventricular fibrillation.

Figure 1. Schematic demonstrating the various mechanisms involved in regulating autonomic balance at the end organ level

Black arrows indicate the action of primary neurotransmitters noradrenaline and acetylcholine. Red (inhibition) and green (potentiation) arrows indicate the action of various co‐transmitters and hormones in modifying autonomic tone. In diseased states such as chronic heart failure and myocardial infection these mechanisms are perturbed, favouring sympathoexcitation and vagal withdrawal. ACh, acetylcholine; AT II, angiotensin II; β1, beta 1 adrenergic receptor; BNP, brain‐natriuretic peptide; CAPON, carboxy‐terminal PDZ ligand of nNOS; CHF, chronic heart failure; CNP, C‐type natriuretic peptide; M2, type 2 muscarinic receptor; MI, myocardial infarction; NA, noradrenaline; nNOS, neuronal nitric oxide synthase; NPY, neuropeptide Y.

Figure 2. Kaplan–Mayer plots

Kaplan–Mayer plots demonstrating cumulative incidence of outcomes in STEMI (n = 163) and heart failure (n = 833) patients according to baseline plasma NPY concentrations. Reproduced from Gibbs et al. (2022) and McDowell et al. (2024). NPY, neuropeptide‐Y; STEMI, ST‐elevation myocardial infarction.

Figure 3. Bar plot comparing mean coronary sinus and peripheral venous NPY concentrations across a spectrum of cardiac disease

‘Non‐flow limiting CAD’ are patients without flow limiting epicardial coronary artery disease at the time of invasive coronary angiography. ‘Flow‐limiting CAD’ are patients who required percutaneous coronary intervention for significant epicardial coronary artery stenosis (including angina and non‐ST elevation myocardial infarction). Reproduced from Herring et al. (2019), Ajijola et al. (2020), Gibbs et al. (2022) and McDowell et al. (2024). CAD: coronary artery disease, CHF: chronic heart failure, NPY: neuropeptide Y, STEMI: ST‐elevation myocardial infarction.