111 research outputs found
Bayliss Starling Prize Lecture 2023: NeuropeptideāY being āunsympatheticā 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 āexcite or arouseā), 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 betaāblockers improve mortality in these conditions by preventing the action of the neurotransmitter noradrenaline, a substantial residual risk remains. Recently, we have identified the sympathetic coātransmitter neuropeptideāY (NPY) as being released during AMI, leading to larger infarcts and lifeāthreatening 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 stateāofātheāart 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. imag
Regulation of hippocampal synaptic plasticity thresholds and changes in exploratory and learning behavior in dominant negative NPR-B mutant rats
The second messenger cyclic GMP affects synaptic transmission and modulates
synaptic plasticity and certain types of learning and memory processes. The
impact of the natriuretic peptide receptor B (NPR-B) and its ligand C-type
natriuretic peptide (CNP), one of several cGMP producing signaling systems, on
hippocampal synaptic plasticity and learning is, however, less well
understood. We have previously shown that the NPR-B ligand CNP increases the
magnitude of long-term depression (LTD) in hippocampal area CA1, while
reducing the induction of long-term potentiation (LTP). We have extended this
line of research to show that bidirectional plasticity is affected in the
opposite way in rats expressing a dominant-negative mutant of NPR-B (NSE-NPR-
BĪKC) lacking the intracellular guanylyl cyclase domain under control of a
promoter for neuron-specific enolase. The brain cells of these transgenic rats
express functional dimers of the NPR-B receptor containing the dominant-
negative NPR-BĪKC mutant, and therefore show decreased CNP-stimulated cGMP-
production in brain membranes. The NPR-B transgenic rats display enhanced LTP
but reduced LTD in hippocampal slices. When the frequency-dependence of
synaptic modification to afferent stimulation in the range of 1ā100 Hz was
assessed in transgenic rats, the threshold for both, LTP and LTD induction,
was shifted to lower frequencies. In parallel, NPR-BĪKC rats exhibited an
enhancement in exploratory and learning behavior. These results indicate that
bidirectional plasticity and learning and memory mechanism are affected in
transgenic rats expressing a dominant-negative mutant of NPR-B. Our data
substantiate the hypothesis that NPR-B-dependent cGMP signaling has a
modulatory role for synaptic information storage and learning
Editorial: Cardiovascular physiology and pathology of cardio-pulmonary and peripheral sensory nerves
Low-Income African American Womenās Perceptions of Primary Care Physician Weight Loss Counseling: A Positive Deviance Study
The Role of Neuropeptide Y in Cardiovascular Health and Disease
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 vasoconstriction, cardiac remodeling, and angiogenesis. It is increasingly also implicated in cardiovascular disease pathogenesis, including hypertension, atherosclerosis, ischemia/infarction, arrhythmia, and heart failure. This review will focus on the physiological and pathogenic role of NPY in the cardiovascular system. After summarizing the NPY receptors which predominantly mediate cardiovascular actions, along with their signaling pathways, individual disease processes will be considered. A thorough understanding of these roles may allow therapeutic targeting of NPY and its receptors
Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential
Ā© 2015 Heart Rhythm Society. Background Bradycardic agents are of interest for the treatment of ischemic heart disease and heart failure, as heart rate is an important determinant of myocardial oxygen consumption. Objectives The purpose of this study was to investigate the propensity of hydroxychloroquine (HCQ) to cause bradycardia. Methods We assessed the effects of HCQ on (1) cardiac beating rate in vitro (mice); (2) the "funny" current (If) in isolated guinea pig sinoatrial node (SAN) myocytes (1, 3, 10 Ī¼M); (3) heart rate and blood pressure in vivo by acute bolus injection (rat, dose range 1-30 mg/kg), (4) blood pressure and ventricular function during feeding (mouse, 100 mg/kg/d for 2 wk, tail cuff plethysmography, anesthetized echocardiography). Results In mouse atria, spontaneous beating rate was significantly (
Blockade of sodiumācalcium exchanger via ORM-10962 attenuates cardiac alternans
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 blockade of the sodiumācalcium exchanger (NCX) could inhibit alternans. The effects of the selective NCX blocker ORM-10962 were evaluated on action potentials measured with microelectrodes from canine papillary muscle preparations, and calcium transients measured using Fluo4-AM from isolated ventricular myocytes paced to evoke alternans. Computer simulations were used to obtain insight into the drug's mechanisms of action. ORM-10962 attenuated cardiac alternans, both in action potential duration and calcium transient amplitude. Three morphological types of alternans were observed, with differential response to ORM-10962 with regards to APD alternans attenuation. Analysis of APD restitution indicates that calcium oscillations underlie alternans formation. Furthermore, ORM-10962 did not markedly alter APD restitution, but increased post-repolarization refractoriness, which may be mediated by indirectly reduced L-type calcium current. Computer simulations reproduced alternans attenuation via ORM-10962, suggesting that it is acts by reducing sarcoplasmic reticulum release refractoriness. This results from the ORM-10962-induced sodiumācalcium exchanger block accompanied by an indirect reduction in L-type calcium current. Using a computer model of a heart failure cell, we furthermore demonstrate that the anti-alternans effect holds also for this disease, in which the risk of alternans is elevated. Targeting NCX may therefore be a useful anti-arrhythmic strategy to specifically prevent calcium driven alternans
Ī²-Adrenergic Receptor Stimulation and Alternans in the Border Zone of a Healed Infarct: An ex vivo Study and Computational Investigation of Arrhythmogenesis
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 the border zone is most vulnerable to alternans, that Ī²-adrenergic receptor stimulation can suppresses this, and investigate the consequences in terms of arrhythmogenic mechanisms.Methods and Results: Anterior MI was induced in Sprague-Dawley rats (n = 8) and allowed to heal over 2 months. This resulted in scar formation, significant (p < 0.05) dilation of the left ventricle, and reduction in ejection fraction compared to sham operated rats (n = 4) on 7 T cardiac magnetic resonance imaging. Dual voltage/calcium optical mapping of post-MI Langendorff perfused hearts (using RH-237 and Rhod2) demonstrated that the border zone was significantly more prone to alternans than the surrounding myocardium at longer cycle lengths, predisposing to spatially heterogeneous alternans. Ī²-Adrenergic receptor stimulation with norepinephrine (1 Ī¼mol/L) attenuated alternans by 60 [52ā65]% [interquartile range] and this was reversed with metoprolol (10 Ī¼mol/L, p = 0.008). These results could be reproduced by computer modeling of the border zone based on our knowledge of Ī²-adrenergic receptor signaling pathways and their influence on intracellular calcium handling and ion channels. Simulations also demonstrated that Ī²-adrenergic receptor stimulation in this specific region reduced the formation of conduction block and the probability of premature ventricular activation propagation.Conclusion: While high levels of overall cardiac sympathetic drive are a negative prognostic indicator of mortality following MI and during heart failure, Ī²-adrenergic receptor stimulation in the infarct border zone reduced spatially heterogeneous alternans, and prevented conduction block and propagation of extrasystoles. This may help explain recent clinical imaging studies using meta-iodobenzylguanidine (MIBG) and 11C-meta-hydroxyephedrine positron emission tomography (PET) which demonstrate that border zone denervation is strongly associated with a high risk of future arrhythmia
Rationale and study design of the MINERVA study: Multicentre Investigation of Novel Electrocardiogram Risk markers in Ventricular Arrhythmia prediction-UK multicentre collaboration
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 defibrillator for primary prevention indication. Methods and analysis Multicentre Investigation of Novel Electrocardiogram Risk markers in Ventricular Arrhythmia prediction is a prospective, open label, single blinded, multicentre observational study to establish the efficacy of two ECG biomarkers in predicting VA risk. 440 participants with ischaemic cardiomyopathy undergoing routine first time implantable cardioverter-defibrillator (ICD) implantation for primary prevention indication are currently being recruited. An electrophysiological (EP) study is performed using a non-invasive programmed electrical stimulation protocol via the implanted device. All participants will undergo the EP study hence no randomisation is required. Participants will be followed up over a minimum of 18 months and up to 3 years. The first patient was recruited in August 2016 and the study will be completed at the final participant follow-up visit. The primary endpoint is ventricular fibrillation or sustained ventricular tachycardia >200 beats/min as recorded by the ICD. The secondary endpoint is SCD. Analysis of the ECG data obtained during the EP study will be performed by the core lab where blinding of patient health status and endpoints will be maintained. Ethics and dissemination Ethical approval has been granted by Research Ethics Committees Northern Ireland (reference no. 16/NI/0069). The results will inform the design of a definitive Randomised Controlled Trial (RCT). Dissemination will include peer reviewed journal articles reporting the qualitative and quantitative results, as well as presentations at conferences and lay summaries
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