Neil Herring

University of Oxford | OX · Department of Physiology, Anatomy and Genetics

Endolysosomes (EL) are known for their role in regulating both intracellular trafficking and proteostasis. EL help facilitate elimination of damaged membrane and cytosolic proteins, protein aggregates, membranous organelles and also play an important role in calcium signalling. Despite the importance of EL, their specific role in cardiovascular dis...

Introduction Left ventricular (LV) pressure-volume (PV) loops provide gold-standard physiological information but require invasive measurements of ventricular intracavity pressure, limiting clinical and research applications. Recent development has seen the introduction of non-invasively computed PV loops from cardiovascular magnetic resonance (CMR...

Haemorrhagic and severe hypovolaemic shock can be rapidly fatal unless identified and resuscitated quickly. Monitoring of haemodynamic and cellular end points is crucial in guiding treatment and improving outcomes. This article therefore focuses on the pathophysiology of hypovolaemic shock, volume resuscitation, haemostasis and approaches to manage...

Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventric...

Background The sympathetic cotransmitter, neuropeptide Y (NPY), is released into the coronary sinus during ST‐segment–elevation myocardial infarction and can constrict the coronary microvasculature. We sought to establish whether peripheral venous (PV) NPY levels, which are easy to obtain and measure, are associated with microvascular obstruction,...

Introduction The failing heart is thought to be metabolically inflexible, and oxygen limited, shifting from free fatty acid (FFA) oxidation towards glucose metabolism. Whilst glucose metabolism is more oxygen efficient, fatty acid (FA) metabolism generates more adenosine triphosphate (ATP) per mole of substrate. Cardiac resynchronisation therapy (C...

Introduction Left ventricular (LV) pressure-volume (PV) loops provide gold-standard physiological information but require invasive measurements of ventricular intracavity pressure, limiting clinical and research applications. Recent development has seen the introduction of non-invasively computed PV loops from cardiovascular magnetic resonance (CMR...

Although cardiac resynchronization therapy (CRT) has become well established in the treatment of heart failure, the management of patients who do not respond after CRT remains a key challenge. This review will summarize what we have learned about non-responders over the last 20 years and discuss methods for optimizing response, including the introd...

The relationship between dietary NaCl intake and high blood pressure is well-established, and occurs primarily through activation of the sympathetic nervous system. Nax, a Na+-sensitive Na+ channel, plays a pivotal role in driving sympathetic excitability, which is thought to originate from central regions controlling neural outflow. We investigate...

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Local Departmental Research Funding Background Cardiac resynchronisation therapy (CRT) using fusion pacing requires correct timing of left ventricular pacing to right ventricular activation. The SyncAV™ algorithm, achieves this by dynamic...

Introduction: The purpose of this study is to assess the ability of two new ECG markers (Regional Repolarisation Instability Index (R2I2) and Peak Electrical Restitution Slope) to predict sudden cardiac death (SCD) or ventricular arrhythmia (VA) events in patients with ischaemic cardiomyopathy undergoing implantation of an implantable cardioverter...

Objective: Although intravenous nitrates are commonly used in clinical medicine, they have been shown to increase myocardial oxygen consumption and inhibit complex IV of the electron transport chain. As such we sought to measure whether myocardial energetics were impaired during glyceryl trinitrate (GTN) infusion. Methods: 10 healthy volunteers und...

Background The rate of left ventricular (LV) lead displacement after cardiac resynchronization therapy (CRT) remains high despite improvements in lead technology. In 2017, a novel quadripolar lead with active fixation technology became available in the UK. Methods This was a retrospective, observational study analysing device complications in 476...

Introduction: Based on the premise that in HFrEF the heart is metabolically inflexible and oxygen limited, current metabolic therapies aim to increase glucose oxidation. However, if the human failing heart is neither inflexible nor oxygen limited, this approach is called into question. Methods: During either insulin-glucose (GI) or Intralipid infus...

Background Measurement of the Phosphocreatine/Adenosine Triphosphate (ATP) ratio along with the Creatine Kinase (CK) rate constant (CK kf ) allows calculation of the ATP delivery rate (CK flux). Metabolic flexibility may be impaired both in heart failure with reduced ejection fraction (HFrEF) and diabetes mellitus (DM). It is unknown to what extent...

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation (BHF) and Local Departmental Research Funding Background Fusion pacing as part of cardiac resynchronization therapy (CRT) requires correct timing of left ventricular pacing to right ventricular activation. The SyncAV algorithm, available...

Optical mapping is widely used in experimental cardiology, as it allows visualization of cardiac membrane potential and calcium transients. However, optical mapping measurements from a single heart or cell culture can produce several gigabytes of data, warranting automated computer analysis. Here we present COSMAS, a software toolkit for automated...

Hydroxychloroquine (HCQ), the hydroxyl derivative of chloroquine (CQ), is widely used in the treatment of rheumatological conditions (systemic lupus erythematosus, rheumatoid arthritis) and is being studied for the treatment and prevention of COVID-19. Here, we investigate through mathematical modelling the safety profile of HCQ, CQ and other QT-pr...

Repolarization alternans, a periodic oscillation of long-short action potential duration, is an important source of arrhythmogenic substrate, although the mechanisms driving it are insufficiently understood. Despite its relevance as an arrhythmia precursor, there are no successful therapies able to target it specifically. We hypothesized that block...

Introduction The Phosphocreatine (PCR)/ATP ratio is an established indicator of cardiac energetic status. Measurement of the Creatine Kinase pseudo-first order rate constant (CKkf) provides a more sensitive measure of cardiac energetics, and allows calculation of ATP delivery rate through the creatine kinase shuttle (CK flux). The normal heart is m...

Cardiac stimulation via sympathetic neurons can potentially trigger arrhythmias. We present approaches to study neuron-cardiomyocyte interactions involving optogenetic selective probing and all-optical electrophysiology to measure activity in an automated fashion. Here we demonstrate the utility of optical interrogation of sympathetic neurons and t...

Neurohumoral activation is an early hallmark of cardiovascular disease and contributes to the etiology of the pathophysiology. Stellectomy has reemerged as a positive therapeutic intervention to modify the progression of dysautonomia, although the biophysical properties underpinning abnormal activity of this ganglia are not fully understood in the...

Aims We investigate mechanisms for potential pro-arrhythmic effects of hydroxychloroquine (HCQ) alone, or combined with azithromycin (AZM), in Covid-19 management supplementing the limited available experimental cardiac safety data. Methods We integrated patch-clamp studies utilizing In Vitro ProArrhythmia Assay (CiPA) Schema IC 50 paradigms, mole...

Importance Chronic heart failure (CHF) is associated with increased sympathetic drive and may increase expression of the cotransmitter neuropeptide Y (NPY) within sympathetic neurons. Objective To determine whether myocardial NPY levels are associated with outcomes in patients with stable CHF. Design, Setting, and Participants Prospective observa...

Aims: ST-elevation myocardial infarction is associated with high levels of cardiac sympathetic drive and release of the co-transmitter neuropeptide Y (NPY). We hypothesized that despite beta-blockade, NPY promotes arrhythmogenesis via ventricular myocyte receptors. Methods and results: In 78 patients treated with primary percutaneous coronary in...

Cardiac sympathetic nerves are hyperactive in many cardiovascular diseases, however, the mechanisms underlying this are unknown. In humans, this phenotype is known to precede the development of hypertension and contribute to the severity of the disease. We highlight an electrophysiological phenotype in post-ganglionic sympathetic stellate ganglia n...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A patient with previous coronary artery bypass grafting developed an iatrogenic pneumothorax, along with pneumopericardium and pneumomediastinum, after elective implantation of a cardiac resynchronization therapy pacemaker. There was no evidence of lead perforation, and the patient remained well and was successfully managed conservatively. We hypot...

Haemorrhagic and severe hypovolaemic shock can be rapidly fatal unless identified and resuscitated quickly. Monitoring of haemodynamic and cellular end points is crucial in guiding treatment and improving outcomes. This article therefore focuses on the pathophysiology of hypovolaemic shock, volume resuscitation, haemostasis and approaches to manage...

Alterations in autonomic function are known to occur in cardiac conditions including sudden cardiac death. Cardiac stimulation via sympathetic neurons can potentially trigger arrhythmias. Dissecting direct neural-cardiac interactions at the cellular level is technically challenging and understudied due to the lack of experimental model systems and...

Research into cardiac autonomic control has received great interest in the past 20 years, and we are now at a critical juncture with regard to the clinical translation of the experimental findings. A rush to develop clinical interventions and implant a range of devices aimed at cardiac neuromodulation therapy has occurred. This interest has been dr...

Background: Following myocardial infarction (MI), the myocardium is prone to calcium-driven alternans, which typically precedes ventricular tachycardia and fibrillation. MI is also associated with remodeling of the sympathetic innervation in the infarct border zone, although how this influences arrhythmogenesis is controversial. We hypothesize that...

Introduction: Cardiac resynchronisation therapy (CRT) is an established treatment modality for patients with symptomatic heart failure associated with a prolonged QRS duration on the electrocardiogram. Despite advances in hardware and programming, up to 30% of patients still do not derive symptomatic benefit. Multipolar left ventricular (LV) leads...

Aims: The co-transmitter neuropeptide-Y (NPY) is released during high sympathetic drive, including ST-elevation myocardial infarction (STEMI), and can be a potent vasoconstrictor. We hypothesized that myocardial NPY levels correlate with reperfusion and subsequent recovery following primary percutaneous coronary intervention (PPCI), and sought to d...

Neuropeptide Y (NPY) is an abundant sympathetic co-transmitter, widely found in the central and peripheral nervous systems and with diverse roles in multiple physiological processes. In the cardiovascular system it is found in neurons supplying the vasculature, cardiomyocytes and endocardium, and is involved in physiological processes including vas...

Background: Cardiac Resynchronization Therapy (CRT) is an effective treatment for selected patients with heart failure, but can be limited by the inability to place the left ventricular (LV) lead via the coronary sinus. Objective: We have developed an alternative approach, placing the LV lead endocardially via an interventricular septal puncture...

AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αβγ complexes, whose regulatory γ subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 subunit exhibit a phenotype including unexplained slowing of heart rate (br...

Reduced cardiomyocyte excitation-contraction coupling and downregulation of the SERCA2a (sarcoendoplasmic reticulum calcium ATPase 2a) is associated with heart failure. This has led to viral transgene upregulation of SERCA2a in cardiomyocytes as a treatment. We hypothesized that SERCA2a gene therapy expressed under a similar promiscuous cytomegalov...

Aims: Endocardial left ventricular (LV) pacing for Cardiac Resynchronization Therapy has been proposed as an alternative to conventional LV lead placement via the coronary sinus. In order to assess the relative benefits and risks of this technique, we have performed a meta-analysis of published reports. Methods and results: A systemic search was...

Haemorrhagic and severe hypovolaemic shock can be rapidly fatal unless identified and resuscitated quickly. Monitoring of haemodynamic and cellular end points is crucial in guiding treatment and improving outcomes. This review therefore focuses on the pathophysiology of hypovolaemic shock, volume resuscitation, haemostasis and approaches to managem...

Aims B-type natriuretic peptide (BNP)-NPR-A receptor signalling inhibits cardiac sympathetic neurotransmission, although, C-type natriuretic peptide (CNP) is the predominant neuropeptide of the nervous system with expression in the heart and vasculature. We hypothesised that CNP acts similarly to BNP, and that transgenic rats (TGR) with neuron spec...

A hallmark of cardiovascular disease is cardiac autonomic dysregulation. The phenotype of impaired parasympathetic responsiveness and sympathetic hyperactivity in experimental animal models is also well documented in large scale human studies in the setting of heart failure and myocardial infarction, and is predictive of morbidity and mortality. De...

Introduction Cardiac Resynchronisation Therapy (CRT) is an effective therapy for selected patients with heart failure, but is limited in some patients by inability to place the left ventricular (LV) lead via the coronary sinus. We have developed an alternative technique, placing the LV lead endocardially through an interventricular septal puncture....

Objectives: The objective of this study was to evaluate the cost-effectiveness of quadripolar versus bipolar cardiac resynchronization defibrillator therapy systems. Background: Quadripolar left ventricular (LV) leads for cardiac resynchronization therapy reduce phrenic nerve stimulation (PNS) and are associated with reduced mortality compared w...

Introduction: Cardiac resynchronisation therapy is an important treatment for heart failure, yet, it is only applicable to patients with left bundle branch block. PR prolongation is associated with increased mortality in heart failure regardless of QRS duration. We have previously demonstrated that AV optimised temporary His pacing improves acute h...

Neuronal elements distributed throughout the cardiac nervous system, from the level of the insular cortex to the intrinsic cardiac nervous system, are in constant communication with one another to assure that cardiac output matches the dynamic process of regional blood flow demand. Neural elements in their various 'levels' become differentially rec...

The nervous system and cardiovascular system develop in concert and are functionally interconnected in both health and disease. This white paper focuses on the cellular and molecular mechanisms that underlie neural-cardiac interactions during development, during normal physiological function in the mature system, and during pathological remodeling...

Beta-blockers are the only anti-arrhythmic drugs that improve mortality post myocardial infarction (MI), but a significant risk of ventricular arrhythmia remains. We have shown that ventricular fibrillation threshold is reduced following high-level sympathetic stimulation even in the presence of a beta-blocker due to release of the sympathetic co-t...

Objectives and Background: In selected patients, cardiac resynchronization therapy (CRT) improves morbidity and mortality, but the placement of the left ventricular (LV) lead can be technically challenging. We aimed to assess contemporary and historical success rates of transvenous LV lead placement for CRT, their change over time, and the reasons...

Aims: Implantable cardiac vagal nerve stimulators are a promising treatment for ventricular arrhythmia in patients with heart failure. Animal studies suggest the antifibrillatory effect may be nitric oxide (NO) dependent, although the exact site of action is controversial. We investigated whether a stable analogue of acetylcholine could raise vent...

Supplementary Material

Supplementary Material

Supplementary Material

Supplementary Material

Medical education like medical science is constantly evolving. Traditional courses often start by focusing on the basic sciences such as physiology, cell biology, biochemistry and anatomy, studying each in isolation. However, medical school teaching is moving to a more systems based approach, often based around the clinical specialties. From the fi...

Medical education like medical science is constantly evolving. Traditional courses often start by focusing on the basic sciences such as physiology, cell biology, biochemistry and anatomy, studying each in isolation. However, medical school teaching is moving to a more systems based approach, often based around the clinical specialties. From the fi...

Medical education like medical science is constantly evolving. Traditional courses often start by focusing on the basic sciences such as physiology, cell biology, biochemistry and anatomy, studying each in isolation. However, medical school teaching is moving to a more systems based approach, often based around the clinical specialties. From the fi...

Medical education like medical science is constantly evolving. Traditional courses often start by focusing on the basic sciences such as physiology, cell biology, biochemistry and anatomy, studying each in isolation. However, medical school teaching is moving to a more systems based approach, often based around the clinical specialties. From the fi...

Medical education like medical science is constantly evolving. Traditional courses often start by focusing on the basic sciences such as physiology, cell biology, biochemistry and anatomy, studying each in isolation. However, medical school teaching is moving to a more systems based approach, often based around the clinical specialties. From the fi...

Medical education like medical science is constantly evolving. Traditional courses often start by focusing on the basic sciences such as physiology, cell biology, biochemistry and anatomy, studying each in isolation. However, medical school teaching is moving to a more systems based approach, often based around the clinical specialties. From the fi...

Medical education like medical science is constantly evolving. Traditional courses often start by focusing on the basic sciences such as physiology, cell biology, biochemistry and anatomy, studying each in isolation. However, medical school teaching is moving to a more systems based approach, often based around the clinical specialties. From the fi...

Medical education like medical science is constantly evolving. Traditional courses often start by focusing on the basic sciences such as physiology, cell biology, biochemistry and anatomy, studying each in isolation. However, medical school teaching is moving to a more systems based approach, often based around the clinical specialties. From the fi...