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

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.

Observational study in healthy volunteers to define interobserver reliability of ultrasound haemodynamic monitoring techniques performed by trainee doctors.

OBJECTIVES: Bedside ultrasound is increasingly being used to guide fluid management in shocked patients. Little data exist on the inter-rater reliability of techniques used, especially when performed by nonexpert trainee doctors. The primary aim of this study is to measure the inter-rater reliability of five ultrasound techniques commonly used to guide fluid management: inferior vena cava collapsibility index (IVCCI), transthoracic echocardiography (TTE)-derived stroke volumes, ultrasound cardiac output monitor (USCOM) derived stroke volume and carotid artery blood flow and corrected flow time measurements. METHODS: Two Royal College of Emergency Medicine level one ultrasound-certified emergency medicine trainees performed paired ultrasound measurements on 31 healthy nonpatient volunteers. Inter-rater reliability was assessed through three indices: interclass correlation coefficient (ICC), limits of agreements (LOAs) derived from Band-Altman plots and the proportion of paired scans with absolute differences of less that 15% (defined as agreement). RESULTS: TTE-derived measurements performed the best overall, with an LOA of 22%, an ICC of 0.55 and an agreement of 80%. USCOM also performed well, with an LOA of 33%, an ICC of 0.68 and an agreement of 58%. IVCCI and carotid artery-derived measurements performed poorly across all indices. CONCLUSION: TTE-derived measurements showed the highest level of inter-rater reliability and can thus be expected to provide reliable measures over time with different sonographer clinicians. USCOM interobserver reliability was also adequate for clinical use. However, on the basis of inter-reliability measures, IVCCI and carotid artery measurements were found to be inadequate for clinical use.

Investigating the ability of non-invasive measures of cardiac output to detect a reduction in blood volume resulting from venesection in spontaneously breathing subjects.

BACKGROUND: Monitoring cardiac output (CO) in shocked patients provides key etiological information and can be used to guide fluid resuscitation to improve patient outcomes. Previously this relied on invasive monitoring, restricting its use in the Emergency Department (ED) setting. The development of non-invasive devices (such as LiDCOrapidv2 with CNAP™ and USCOM 1A), and ultrasound based measurements (Transthoracic echocardiography, inferior vena cava collapsibility index (IVCCI), carotid artery blood flow (CABF) and carotid artery corrected flow time (FTc)) enables stroke volume (SV) and CO to be measured non-invasively in the ED. We investigated the ability of these techniques to detect a change in CO resulting from a 500 ml reduction in circulating blood volume (CBV) following venesection in spontaneously breathing subjects. Additionally, we investigated if using incentive spirometry to standardise inspiratory effort improved the accuracy of IVC based measurements in spontaneously breathing subjects. METHODS: We recorded blood pressure, heart rate, IVCCI, CABF, FTc, transthoracic echocardiographic (TTE) SV and CO, USCOM 1A SV and CO, LIDCOrapidv2 SV, CO, Stroke volume variation (SVV) and pulse pressure variation (PPV) in 40 subjects immediately before and after venesection. The Log-Odds and coefficient of variation of the difference between pre- and post-venesection values for each technique were used to compare their ability to consistently detect CO changes resulting from a reduction in CBV resulting from venesection. RESULTS: TTE consistently detected a reduction in CO associated with venesection with an average decrease in measured CO of 0.86 L/min (95% CI 0.61 to 1.12) across subjects. None of the other investigated techniques changed in a consistent manner following venesection. The use of incentive spirometry improved the consistency with which IVC ultrasound was able to detect a reduction in CBV. CONCLUSIONS: In a population of spontaneously breathing patients, TTE is able to consistency detect a reduction in CO associated with venesection.

Modelling the initial phase of the human rod photoreceptor response to the onset of steady illumination.

The initial time course of the change in photoreceptor outer segment membrane conductance in response to light flashes has been modelled using biochemical analysis of phototransduction, and the model has been successfully applied to a range of in vitro recordings and has also been shown to provide a good fit to the leading edge of the electroretinogram a-wave recorded in vivo. We investigated whether a simple modification of the model's equation would predict responses to the onset of steady illumination and tested this against electroretinogram recordings. Scotopic electroretinograms were recorded from three normal human subjects, using conductive fibre electrodes, in response to light flashes (0.30-740 scotopic cd m(-2) s) and to the onset of steady light (11-1,900 scotopic cd m(-2)). Subjects' pupils were dilated pharmacologically. The standard form of the model was applied to flash responses, as in previous studies, to obtain values for the three parameters: maximal response amplitude r (max), sensitivity S and effective delay time t (eff). A new "step response" equation was derived, and this equation provided a good fit to rod responses to steps of light using the same parameter values as for the flash responses. The results support the applicability of the model to the leading edge of electroretinogram responses: in each subject, the model could be used to fit responses both to flashes of light and to the onset of backgrounds with a single set of parameter values.