An Ovine Model of Chronic Heart Failure Induced by Repeated Coronary Microembolizations.

The use of large animals in research provides a unique bridge between preclinical findings and clinical relevance, offering a valuable perspective for advancing our understanding of the complexities of heart failure. Multiple models of heart failure have been established with advantages and limitations of each model. Many insights have been gained from these models for understanding both pathophysiological mechanisms and therapeutic interventions for heart failure.

Mechanical circulatory support reduces renal sympathetic nerve activity in an ovine model of acute myocardial infarction.

Purpose: The use of circulatory assist devices has been shown to improve glomerular filtration rate and reduce the incidence of acute kidney injury in patients following acute cardiac pathology. However, the mechanisms of improvement in kidney function are not clear. We tested the hypothesis that mechanical circulatory support would result in a decrease in directly recorded renal sympathetic nerve activity (RSNA) and mediate the improvement in renal blood flow (RBF) in a setting of acute myocardial infarction (AMI)-induced left ventricular systolic dysfunction.

The sympathetic nervous system in heart failure with preserved ejection fraction.

The sympathetic nervous system (SNS) is a major mediator of cardiovascular physiology during exercise in healthy people. However, its role in heart failure with preserved ejection fraction (HFpEF), where exercise intolerance is a cardinal symptom, has remained relatively unexplored. The present review summarizes and critically explores the currently limited data on SNS changes in HFpEF patients with a particular emphasis on caveats of the data and the implications for its subsequent interpretation.

Cardiac Vagal Nerve Activity Increases During Exercise to Enhance Coronary Blood Flow.

Background: The phrase complete vagal withdrawal is often used when discussing autonomic control of the heart during exercise. However, more recent studies have challenged this assumption. We hypothesized that cardiac vagal activity increases during exercise and maintains cardiac function via transmitters other than acetylcholine.

Neural control of coronary artery blood flow by non-adrenergic and non-cholinergic mechanisms.

Blood flow through the coronary vasculature is essential to maintain myocardial function. As the metabolic demand of the heart increases, so does blood flow through the coronary arteries in a dynamic and adaptive manner. Several mechanisms, including local metabolic factors, mechanical forces and autonomic neural control, regulate coronary artery blood flow.

Role of the angiotensin type 1 receptor in modulating the carotid chemoreflex in an ovine model of renovascular hypertension.

Objective: The carotid body has been implicated as an important mediator and putative target for hypertension. Previous studies have indicated an important role for angiotensin II in mediating carotid body function via angiotensin type-1 receptors (AT1R); however, their role in modulating carotid body function during hypertension is unclear.

Methods: Using a large preclinical ovine model of renovascular hypertension, we hypothesized that acute AT1R blockade would lower blood pressure and decrease carotid body-mediated increases in arterial pressure.

Aortic Body Chemoreceptors Regulate Coronary Blood Flow in Conscious Control and Hypertensive Sheep.

Background: Peripheral arterial chemoreceptors monitor the chemical composition of arterial blood and include both the carotid and aortic bodies (ABs). While the role of the carotid bodies has been extensively studied, the physiological role of the ABs remains relatively under-studied, and its role in hypertension is unexplored. We hypothesized that activation of the ABs would increase coronary blood flow in the normotensive state and that this would be mediated by the parasympathetic nerves to the heart.

Reverse re-modelling chronic heart failure by reinstating heart rate variability.

Heart rate variability (HRV) is a crucial indicator of cardiovascular health. Low HRV is correlated with disease severity and mortality in heart failure. Heart rate increases and decreases with each breath in normal physiology termed respiratory sinus arrhythmia (RSA).

Mathematical modelling of atrial and ventricular pressure-volume dynamics and their change with heart rate.

This paper presents mathematical models that can simulate the cardiovascular system of a healthy sheep under normal resting conditions in which the heart rate changes significantly. The models include several new modelling features that are introduced progressively. The contraction of the cardiac chambers is modelled using a time-dependent muscle force with constant elasticity instead of time dependent elasticity.

Angiotensin II and the Cardiac Parasympathetic Nervous System in Hypertension.

The renin-angiotensin-aldosterone system (RAAS) impacts cardiovascular homeostasis via direct actions on peripheral blood vessels and via modulation of the autonomic nervous system. To date, research has primarily focused on the actions of the RAAS on the sympathetic nervous system. Here, we review the critical role of the RAAS on parasympathetic nerve function during normal physiology and its role in cardiovascular disease, focusing on hypertension.

Regulation of Coronary Blood Flow by the Carotid Body Chemoreceptors in Ovine Heart Failure.

Carotid bodies (CBs) are peripheral chemoreceptors, which are primary sensors of systemic hypoxia and their activation produces respiratory, autonomic, and cardiovascular adjustments critical for body homeostasis. We have previously shown that carotid chemoreceptor stimulation increases directly recorded cardiac sympathetic nerve activity (cardiac SNA) which increases coronary blood flow (CoBF) in conscious normal sheep. Previous studies have shown that chemoreflex sensitivity is augmented in heart failure (HF).

Intracranial baroreflex is attenuated in an ovine model of renovascular hypertension.

We have previously shown that elevations in intracranial pressure (ICP) within physiological ranges in normotensive animals increase arterial pressure; termed the intracranial baroreflex. Hypertension is associated with alterations in reflexes which maintain arterial pressure however, whether the intracranial baroreflex is altered is not known. Hence, in the present study, we tested the hypothesis that in hypertension, physiological increases in ICP would not be accompanied with an increase in arterial pressure.

Activation of the carotid body increases directly recorded cardiac sympathetic nerve activity and coronary blood flow in conscious sheep.

Activation of the carotid body (CB) using intracarotid potassium cyanide (KCN) injection increases coronary blood flow (CoBF). This increase in CoBF is considered to be mediated by co-activation of both the sympathetic and parasympathetic nerves to the heart. However, whether cardiac sympathetic nerve activity (cardiac SNA) actually increases during CB activation has not been determined previously.

Role of the Carotid Body in an Ovine Model of Renovascular Hypertension.

The carotid body is implicated as an important mediator and potential treatment target for hypertension. The mechanisms driving increased carotid body tonicity in hypertension are incompletely understood. Using a large preclinical animal model, which is crucial for translation, we hypothesized that carotid sinus nerve denervation would chronically decrease blood pressure in a renovascular ovine model of hypertension in which hypertonicity of the carotid body is associated with reduced common carotid artery blood flow.

Impaired Baroreflex Function in an Ovine Model of Chronic Heart Failure Induced by Multiple Coronary Microembolizations.

Testing new therapies in heart failure (HF) requires a chronic stable model of HF in large animals. Microembolization of the coronary arteries has been used to model HF previously; however, neural control has not been previously explored in this model. Thus the aim of this study was to further characterize neural control in this model of HF.

Intrathecal Administration of Losartan Reduces Directly Recorded Cardiac Sympathetic Nerve Activity in Ovine Heart Failure.

Early and preferential activation of cardiac sympathetic nerve activity (CSNA) is one of the strongest prognostic markers of heart failure (HF) in patients. Our previous studies have implicated central angiotensin mechanisms as playing a critical role in generating this increase in cardiac sympathetic drive. However, it is unclear if inhibition of ATR (angiotensin type-1 receptors) in different neural groups in the sympathetic pathway to the heart, such as the sympathetic preganglionic neurons in the intermediolateral column of the spinal cord, can reduce cardiac sympathetic drive.

Neurohumoral interactions contributing to renal vasoconstriction and decreased renal blood flow in heart failure.

In heart failure (HF), increases in renal sympathetic nerve activity (RSNA), renal norepinephrine spillover, and renin release cause renal vasoconstriction, which may contribute to the cardiorenal syndrome. To increase our understanding of the mechanisms causing renal vasoconstriction in HF, we investigated the interactions between the increased activity of the renal nerves and the renal release of norepinephrine and renin in an ovine pacing-induced model of HF compared with healthy sheep. In addition, we determined the level of renal angiotensin type-1 receptors and the renal vascular responsiveness to stimulation of the renal nerves and α-adrenoceptors.

Intracranial pressure influences the level of sympathetic tone.

Sympathetic overdrive is associated with many diseases, but its origin remains an enigma. An emerging hypothesis in the development of cardiovascular disease is that the brain puts the utmost priority on maintaining its own blood supply; even if this comes at the "cost" of high blood pressure to the rest of the body. A critical step in making a causative link between reduced brain blood flow and cardiovascular disease is how changes in cerebral perfusion affect the sympathetic nervous system.

Increased cardiac sympathetic nerve activity in ovine heart failure is reduced by lesion of the area postrema, but not lamina terminalis.

Increased cardiac sympathetic nerve activity (CSNA) is a key feature of heart failure (HF) and is associated with poor outcome. There is evidence that central angiotensinergic mechanisms contribute to the increased CSNA in HF, but the central sites involved are unknown. In an ovine, rapid pacing model of HF, we investigated the contribution of the lamina terminalis and area postrema to the increased CSNA and also the responses to fourth ventricular infusion of the angiotensin type 1 receptor antagonist losartan.

Mechanisms underlying the increased cardiac norepinephrine spillover in heart failure.

Patients with heart failure (HF) have increased levels of cardiac norepinephrine (NE) spillover, which is an independent predictor of mortality. We hypothesized that this increase in NE spillover in HF depends not only on increases in sympathetic nerve activity (SNA) but also on changes in the mechanisms controlling NE release and reuptake. Such changes would lead to differences between the increases in directly recorded SNA and NE spillover to the heart in HF.

Direct Recording of Cardiac and Renal Sympathetic Nerve Activity Shows Differential Control in Renovascular Hypertension.

There is increasing evidence that hypertension is initiated and maintained by elevated sympathetic tone. Increased sympathetic drive to the heart is linked to cardiac hypertrophy in hypertension and worsens prognosis. However, cardiac sympathetic nerve activity (SNA) has not previously been directly recorded in hypertension.

Cardiorespiratory interactions in humans and animals: rhythms for life.

The cardiorespiratory system exhibits oscillations from a range of sources. One of the most studied oscillations is heart rate variability, which is thought to be beneficial and can serve as an index of a healthy cardiovascular system. Heart rate variability is dampened in many diseases including depression, autoimmune diseases, hypertension, and heart failure.

Evaluating the carotid bodies and renal nerves as therapeutic targets for hypertension.

Despite the plethora of current treatment options, hypertension remains a difficult condition to adequately control, and there is a pressing need for novel therapeutic strategies. The carotid body has recently become the focus of considerable interest as a potential novel treatment target in essential hypertension. Herein, we appraise the current literature suggesting that the carotid body plays an important causative role to generate sympathetic overactivity and drive increases in arterial pressure, in animal models of hypertension.